Lecture 2 - Disperse Systems

94
1 Pharmaceutics 356C Chapter 14 Disperse Systems (Suspensions, Emulsions, Surfactants, and Aerosols)

Transcript of Lecture 2 - Disperse Systems

Page 1: Lecture 2 - Disperse Systems

1

Pharmaceutics 356C

Chapter 14

Disperse Systems(Suspensions Emulsions Surfactants and Aerosols)

2

Disperse or Polyphase Systemsbull Definition A dispersion is a system containing one

or more constituents distributed throughout a homogeneous medium

bull Can classify dispersions into three categories based on particle size ndash True Solutionsmdashless than 0001 micron ndash Colloidsmdash0001 to 05 microns ndash Coarse Dispersionsmdashgreater than 05 microns

(Much overlapping in such a classification)

3

Disperse or Polyphase Systemsbull True Solutions

ndash Molecular dispersions ndash Particles are invisible even with the electron microscope and

pass through filter paper and semi- permeable membranes bull Colloidal Dispersions (Sols)

ndash An intermediate state between true solutions and suspensions ndash Particles cannot be seen with an ordinary microscope but can

be seen with the electron microscope ndash In addition while the particles of a colloidal dispersion will still

pass through filter paper they will not pass through semi-permeable membranes

ndash Very high surface areandash Particles diffuse more slowly than those of a true solution

4

Disperse or Polyphase Systems

bull Coarse Dispersions ndash The systems we know as emulsions or

suspensionsndash Particles (dispersed phase) are often visible with

the naked eye (unaided)ndash Will not pass through filter paper or semi-

permeable membranesndash Particles seldom diffuse ndash Are used extensively in pharmaceutical products

5

Types of Colloidal Systems

bull There can be many types of colloidal dispersions bull Each phase may be a solid liquid or gas bull The most important colloidal pharmaceutical

preparations include ndash 1 Foams ndash 2 Aerosolsndash 3 Emulsions ndash 4 Suspensions ndash 5 Ointments ndash 6 Gels ndash 7 Magmas and Mucilages

6

Basis of Classification

bull In general colloids may be divided into three main groups

bull This division is made on the basis of how the colloidal particles react with the dispersion medium

7

Basis of Classificationndash Lyophilic (or Hydrophilic Colloid)

bull Solvent lovingmdashattraction to dispersion medium (water or alcohol) ndash hydrophilic alcophilic

ndash Natural Polymers (and charge)raquo Acacia (-) Tragacanth (-) Xanthan Gum (-) Protamines

(+)ndash Cellulose Derivatives (and charge)

raquo Methylcellulose (none) Sodium Carboxymethylcellulose (-)ndash Synthetic Polymers (and charge)

raquo PVP (none) Carbomer (-)ndash Particulate Colloids (and charge)

raquo Bentonite (colloidal hydrated aluminum silicate) (-) Veegum (colloidal aluminum magnesium silicate) (-)

8

Basis of Classificationndash Lyophobic (or Hydrophobic Colloid)

bull Low attraction to dispersion mediummdashmust put a lot of energy into system

bull Requires special method to manufacture ndash Particle size reduction or particle condensation by

aggregation

ndash Association Colloidsbull Amphiphilic colloids (polar and nonpolar parts of

molecule)bull Decrease surface tension (surfactants)

9

Preparation of Colloids

bull Hydrophilic colloidal dispersionsndash Spontaneously disperse no special methods

bull Hydrophobic colloidal dispersionsndash Ultrasonic generators

bull gt20000 Hzndash Colloid mills

bull Less efficient broad particle size distribution

10

Colloid Mill

11

Properties of Colloids

bull Kinetic Propertiesndash Brownian movement

bull Random movement of particles in dispersionbull Observed by SEMbull Due to bombardment of small particles by

molecules of dispersion medium

12

Properties of Colloids

bull Optical propertiesndash Tyndall effect ndash light scatteringndash True solution ndash no visible conendash Colloid ndash visible cone due to light scatteringndash Hydrophilic colloids have less pronounced

Tyndall effect than hydrophobic colloids

13Light through mist from ultrasonic nebulizer

14

Light through colloidal dispersion of silver

15

Properties of Colloidsbull Diffusion

ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law

ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across

plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)

ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions

16

Properties of Colloids

bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where

v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium

17

Properties of Colloidsbull Viscosity

ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate

ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx

bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between

platesbull Often plotted dvdx = 1 (FA)

(fluidity)

ndash Unit of viscosity ndash centipoise (cPs)

18

Shearing force required to produce velocity gradient between parallel

plates of a block material

F

dx

A

dv

Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid

19

Properties of Colloids - Flowndash Newtonian Flow

ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples

raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil

20

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

21

Properties of Colloids - Flowndash Non-Newtonian Flow

bull Plastic Flowndash Apparent viscosity decreases with increasing rates of

shearndash Van der Waals attractive forces must be overcome for

flow to startndash Yield value ndash material begins to flow when forces

between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached

ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)

ndash Flocculated particles in suspension are characteristic of plastic flow

22

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

23

Properties of Colloids

ndash Non-Newtonian Flowbull Pseudoplastic Flow

ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth

Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain

molecules begin to align themselves in direction of flow to reduce internal resistance

24

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

25

Properties of Colloids

ndash Non-Newtonian Flowbull Dilatant

ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is

increased with agitationndash Examples include dispersions with gt50 solids of small

deflocculated particles pastes

26

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 2: Lecture 2 - Disperse Systems

2

Disperse or Polyphase Systemsbull Definition A dispersion is a system containing one

or more constituents distributed throughout a homogeneous medium

bull Can classify dispersions into three categories based on particle size ndash True Solutionsmdashless than 0001 micron ndash Colloidsmdash0001 to 05 microns ndash Coarse Dispersionsmdashgreater than 05 microns

(Much overlapping in such a classification)

3

Disperse or Polyphase Systemsbull True Solutions

ndash Molecular dispersions ndash Particles are invisible even with the electron microscope and

pass through filter paper and semi- permeable membranes bull Colloidal Dispersions (Sols)

ndash An intermediate state between true solutions and suspensions ndash Particles cannot be seen with an ordinary microscope but can

be seen with the electron microscope ndash In addition while the particles of a colloidal dispersion will still

pass through filter paper they will not pass through semi-permeable membranes

ndash Very high surface areandash Particles diffuse more slowly than those of a true solution

4

Disperse or Polyphase Systems

bull Coarse Dispersions ndash The systems we know as emulsions or

suspensionsndash Particles (dispersed phase) are often visible with

the naked eye (unaided)ndash Will not pass through filter paper or semi-

permeable membranesndash Particles seldom diffuse ndash Are used extensively in pharmaceutical products

5

Types of Colloidal Systems

bull There can be many types of colloidal dispersions bull Each phase may be a solid liquid or gas bull The most important colloidal pharmaceutical

preparations include ndash 1 Foams ndash 2 Aerosolsndash 3 Emulsions ndash 4 Suspensions ndash 5 Ointments ndash 6 Gels ndash 7 Magmas and Mucilages

6

Basis of Classification

bull In general colloids may be divided into three main groups

bull This division is made on the basis of how the colloidal particles react with the dispersion medium

7

Basis of Classificationndash Lyophilic (or Hydrophilic Colloid)

bull Solvent lovingmdashattraction to dispersion medium (water or alcohol) ndash hydrophilic alcophilic

ndash Natural Polymers (and charge)raquo Acacia (-) Tragacanth (-) Xanthan Gum (-) Protamines

(+)ndash Cellulose Derivatives (and charge)

raquo Methylcellulose (none) Sodium Carboxymethylcellulose (-)ndash Synthetic Polymers (and charge)

raquo PVP (none) Carbomer (-)ndash Particulate Colloids (and charge)

raquo Bentonite (colloidal hydrated aluminum silicate) (-) Veegum (colloidal aluminum magnesium silicate) (-)

8

Basis of Classificationndash Lyophobic (or Hydrophobic Colloid)

bull Low attraction to dispersion mediummdashmust put a lot of energy into system

bull Requires special method to manufacture ndash Particle size reduction or particle condensation by

aggregation

ndash Association Colloidsbull Amphiphilic colloids (polar and nonpolar parts of

molecule)bull Decrease surface tension (surfactants)

9

Preparation of Colloids

bull Hydrophilic colloidal dispersionsndash Spontaneously disperse no special methods

bull Hydrophobic colloidal dispersionsndash Ultrasonic generators

bull gt20000 Hzndash Colloid mills

bull Less efficient broad particle size distribution

10

Colloid Mill

11

Properties of Colloids

bull Kinetic Propertiesndash Brownian movement

bull Random movement of particles in dispersionbull Observed by SEMbull Due to bombardment of small particles by

molecules of dispersion medium

12

Properties of Colloids

bull Optical propertiesndash Tyndall effect ndash light scatteringndash True solution ndash no visible conendash Colloid ndash visible cone due to light scatteringndash Hydrophilic colloids have less pronounced

Tyndall effect than hydrophobic colloids

13Light through mist from ultrasonic nebulizer

14

Light through colloidal dispersion of silver

15

Properties of Colloidsbull Diffusion

ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law

ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across

plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)

ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions

16

Properties of Colloids

bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where

v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium

17

Properties of Colloidsbull Viscosity

ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate

ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx

bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between

platesbull Often plotted dvdx = 1 (FA)

(fluidity)

ndash Unit of viscosity ndash centipoise (cPs)

18

Shearing force required to produce velocity gradient between parallel

plates of a block material

F

dx

A

dv

Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid

19

Properties of Colloids - Flowndash Newtonian Flow

ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples

raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil

20

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

21

Properties of Colloids - Flowndash Non-Newtonian Flow

bull Plastic Flowndash Apparent viscosity decreases with increasing rates of

shearndash Van der Waals attractive forces must be overcome for

flow to startndash Yield value ndash material begins to flow when forces

between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached

ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)

ndash Flocculated particles in suspension are characteristic of plastic flow

22

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

23

Properties of Colloids

ndash Non-Newtonian Flowbull Pseudoplastic Flow

ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth

Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain

molecules begin to align themselves in direction of flow to reduce internal resistance

24

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

25

Properties of Colloids

ndash Non-Newtonian Flowbull Dilatant

ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is

increased with agitationndash Examples include dispersions with gt50 solids of small

deflocculated particles pastes

26

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 3: Lecture 2 - Disperse Systems

3

Disperse or Polyphase Systemsbull True Solutions

ndash Molecular dispersions ndash Particles are invisible even with the electron microscope and

pass through filter paper and semi- permeable membranes bull Colloidal Dispersions (Sols)

ndash An intermediate state between true solutions and suspensions ndash Particles cannot be seen with an ordinary microscope but can

be seen with the electron microscope ndash In addition while the particles of a colloidal dispersion will still

pass through filter paper they will not pass through semi-permeable membranes

ndash Very high surface areandash Particles diffuse more slowly than those of a true solution

4

Disperse or Polyphase Systems

bull Coarse Dispersions ndash The systems we know as emulsions or

suspensionsndash Particles (dispersed phase) are often visible with

the naked eye (unaided)ndash Will not pass through filter paper or semi-

permeable membranesndash Particles seldom diffuse ndash Are used extensively in pharmaceutical products

5

Types of Colloidal Systems

bull There can be many types of colloidal dispersions bull Each phase may be a solid liquid or gas bull The most important colloidal pharmaceutical

preparations include ndash 1 Foams ndash 2 Aerosolsndash 3 Emulsions ndash 4 Suspensions ndash 5 Ointments ndash 6 Gels ndash 7 Magmas and Mucilages

6

Basis of Classification

bull In general colloids may be divided into three main groups

bull This division is made on the basis of how the colloidal particles react with the dispersion medium

7

Basis of Classificationndash Lyophilic (or Hydrophilic Colloid)

bull Solvent lovingmdashattraction to dispersion medium (water or alcohol) ndash hydrophilic alcophilic

ndash Natural Polymers (and charge)raquo Acacia (-) Tragacanth (-) Xanthan Gum (-) Protamines

(+)ndash Cellulose Derivatives (and charge)

raquo Methylcellulose (none) Sodium Carboxymethylcellulose (-)ndash Synthetic Polymers (and charge)

raquo PVP (none) Carbomer (-)ndash Particulate Colloids (and charge)

raquo Bentonite (colloidal hydrated aluminum silicate) (-) Veegum (colloidal aluminum magnesium silicate) (-)

8

Basis of Classificationndash Lyophobic (or Hydrophobic Colloid)

bull Low attraction to dispersion mediummdashmust put a lot of energy into system

bull Requires special method to manufacture ndash Particle size reduction or particle condensation by

aggregation

ndash Association Colloidsbull Amphiphilic colloids (polar and nonpolar parts of

molecule)bull Decrease surface tension (surfactants)

9

Preparation of Colloids

bull Hydrophilic colloidal dispersionsndash Spontaneously disperse no special methods

bull Hydrophobic colloidal dispersionsndash Ultrasonic generators

bull gt20000 Hzndash Colloid mills

bull Less efficient broad particle size distribution

10

Colloid Mill

11

Properties of Colloids

bull Kinetic Propertiesndash Brownian movement

bull Random movement of particles in dispersionbull Observed by SEMbull Due to bombardment of small particles by

molecules of dispersion medium

12

Properties of Colloids

bull Optical propertiesndash Tyndall effect ndash light scatteringndash True solution ndash no visible conendash Colloid ndash visible cone due to light scatteringndash Hydrophilic colloids have less pronounced

Tyndall effect than hydrophobic colloids

13Light through mist from ultrasonic nebulizer

14

Light through colloidal dispersion of silver

15

Properties of Colloidsbull Diffusion

ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law

ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across

plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)

ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions

16

Properties of Colloids

bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where

v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium

17

Properties of Colloidsbull Viscosity

ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate

ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx

bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between

platesbull Often plotted dvdx = 1 (FA)

(fluidity)

ndash Unit of viscosity ndash centipoise (cPs)

18

Shearing force required to produce velocity gradient between parallel

plates of a block material

F

dx

A

dv

Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid

19

Properties of Colloids - Flowndash Newtonian Flow

ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples

raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil

20

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

21

Properties of Colloids - Flowndash Non-Newtonian Flow

bull Plastic Flowndash Apparent viscosity decreases with increasing rates of

shearndash Van der Waals attractive forces must be overcome for

flow to startndash Yield value ndash material begins to flow when forces

between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached

ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)

ndash Flocculated particles in suspension are characteristic of plastic flow

22

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

23

Properties of Colloids

ndash Non-Newtonian Flowbull Pseudoplastic Flow

ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth

Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain

molecules begin to align themselves in direction of flow to reduce internal resistance

24

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

25

Properties of Colloids

ndash Non-Newtonian Flowbull Dilatant

ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is

increased with agitationndash Examples include dispersions with gt50 solids of small

deflocculated particles pastes

26

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 4: Lecture 2 - Disperse Systems

4

Disperse or Polyphase Systems

bull Coarse Dispersions ndash The systems we know as emulsions or

suspensionsndash Particles (dispersed phase) are often visible with

the naked eye (unaided)ndash Will not pass through filter paper or semi-

permeable membranesndash Particles seldom diffuse ndash Are used extensively in pharmaceutical products

5

Types of Colloidal Systems

bull There can be many types of colloidal dispersions bull Each phase may be a solid liquid or gas bull The most important colloidal pharmaceutical

preparations include ndash 1 Foams ndash 2 Aerosolsndash 3 Emulsions ndash 4 Suspensions ndash 5 Ointments ndash 6 Gels ndash 7 Magmas and Mucilages

6

Basis of Classification

bull In general colloids may be divided into three main groups

bull This division is made on the basis of how the colloidal particles react with the dispersion medium

7

Basis of Classificationndash Lyophilic (or Hydrophilic Colloid)

bull Solvent lovingmdashattraction to dispersion medium (water or alcohol) ndash hydrophilic alcophilic

ndash Natural Polymers (and charge)raquo Acacia (-) Tragacanth (-) Xanthan Gum (-) Protamines

(+)ndash Cellulose Derivatives (and charge)

raquo Methylcellulose (none) Sodium Carboxymethylcellulose (-)ndash Synthetic Polymers (and charge)

raquo PVP (none) Carbomer (-)ndash Particulate Colloids (and charge)

raquo Bentonite (colloidal hydrated aluminum silicate) (-) Veegum (colloidal aluminum magnesium silicate) (-)

8

Basis of Classificationndash Lyophobic (or Hydrophobic Colloid)

bull Low attraction to dispersion mediummdashmust put a lot of energy into system

bull Requires special method to manufacture ndash Particle size reduction or particle condensation by

aggregation

ndash Association Colloidsbull Amphiphilic colloids (polar and nonpolar parts of

molecule)bull Decrease surface tension (surfactants)

9

Preparation of Colloids

bull Hydrophilic colloidal dispersionsndash Spontaneously disperse no special methods

bull Hydrophobic colloidal dispersionsndash Ultrasonic generators

bull gt20000 Hzndash Colloid mills

bull Less efficient broad particle size distribution

10

Colloid Mill

11

Properties of Colloids

bull Kinetic Propertiesndash Brownian movement

bull Random movement of particles in dispersionbull Observed by SEMbull Due to bombardment of small particles by

molecules of dispersion medium

12

Properties of Colloids

bull Optical propertiesndash Tyndall effect ndash light scatteringndash True solution ndash no visible conendash Colloid ndash visible cone due to light scatteringndash Hydrophilic colloids have less pronounced

Tyndall effect than hydrophobic colloids

13Light through mist from ultrasonic nebulizer

14

Light through colloidal dispersion of silver

15

Properties of Colloidsbull Diffusion

ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law

ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across

plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)

ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions

16

Properties of Colloids

bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where

v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium

17

Properties of Colloidsbull Viscosity

ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate

ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx

bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between

platesbull Often plotted dvdx = 1 (FA)

(fluidity)

ndash Unit of viscosity ndash centipoise (cPs)

18

Shearing force required to produce velocity gradient between parallel

plates of a block material

F

dx

A

dv

Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid

19

Properties of Colloids - Flowndash Newtonian Flow

ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples

raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil

20

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

21

Properties of Colloids - Flowndash Non-Newtonian Flow

bull Plastic Flowndash Apparent viscosity decreases with increasing rates of

shearndash Van der Waals attractive forces must be overcome for

flow to startndash Yield value ndash material begins to flow when forces

between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached

ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)

ndash Flocculated particles in suspension are characteristic of plastic flow

22

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

23

Properties of Colloids

ndash Non-Newtonian Flowbull Pseudoplastic Flow

ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth

Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain

molecules begin to align themselves in direction of flow to reduce internal resistance

24

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

25

Properties of Colloids

ndash Non-Newtonian Flowbull Dilatant

ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is

increased with agitationndash Examples include dispersions with gt50 solids of small

deflocculated particles pastes

26

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 5: Lecture 2 - Disperse Systems

5

Types of Colloidal Systems

bull There can be many types of colloidal dispersions bull Each phase may be a solid liquid or gas bull The most important colloidal pharmaceutical

preparations include ndash 1 Foams ndash 2 Aerosolsndash 3 Emulsions ndash 4 Suspensions ndash 5 Ointments ndash 6 Gels ndash 7 Magmas and Mucilages

6

Basis of Classification

bull In general colloids may be divided into three main groups

bull This division is made on the basis of how the colloidal particles react with the dispersion medium

7

Basis of Classificationndash Lyophilic (or Hydrophilic Colloid)

bull Solvent lovingmdashattraction to dispersion medium (water or alcohol) ndash hydrophilic alcophilic

ndash Natural Polymers (and charge)raquo Acacia (-) Tragacanth (-) Xanthan Gum (-) Protamines

(+)ndash Cellulose Derivatives (and charge)

raquo Methylcellulose (none) Sodium Carboxymethylcellulose (-)ndash Synthetic Polymers (and charge)

raquo PVP (none) Carbomer (-)ndash Particulate Colloids (and charge)

raquo Bentonite (colloidal hydrated aluminum silicate) (-) Veegum (colloidal aluminum magnesium silicate) (-)

8

Basis of Classificationndash Lyophobic (or Hydrophobic Colloid)

bull Low attraction to dispersion mediummdashmust put a lot of energy into system

bull Requires special method to manufacture ndash Particle size reduction or particle condensation by

aggregation

ndash Association Colloidsbull Amphiphilic colloids (polar and nonpolar parts of

molecule)bull Decrease surface tension (surfactants)

9

Preparation of Colloids

bull Hydrophilic colloidal dispersionsndash Spontaneously disperse no special methods

bull Hydrophobic colloidal dispersionsndash Ultrasonic generators

bull gt20000 Hzndash Colloid mills

bull Less efficient broad particle size distribution

10

Colloid Mill

11

Properties of Colloids

bull Kinetic Propertiesndash Brownian movement

bull Random movement of particles in dispersionbull Observed by SEMbull Due to bombardment of small particles by

molecules of dispersion medium

12

Properties of Colloids

bull Optical propertiesndash Tyndall effect ndash light scatteringndash True solution ndash no visible conendash Colloid ndash visible cone due to light scatteringndash Hydrophilic colloids have less pronounced

Tyndall effect than hydrophobic colloids

13Light through mist from ultrasonic nebulizer

14

Light through colloidal dispersion of silver

15

Properties of Colloidsbull Diffusion

ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law

ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across

plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)

ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions

16

Properties of Colloids

bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where

v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium

17

Properties of Colloidsbull Viscosity

ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate

ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx

bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between

platesbull Often plotted dvdx = 1 (FA)

(fluidity)

ndash Unit of viscosity ndash centipoise (cPs)

18

Shearing force required to produce velocity gradient between parallel

plates of a block material

F

dx

A

dv

Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid

19

Properties of Colloids - Flowndash Newtonian Flow

ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples

raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil

20

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

21

Properties of Colloids - Flowndash Non-Newtonian Flow

bull Plastic Flowndash Apparent viscosity decreases with increasing rates of

shearndash Van der Waals attractive forces must be overcome for

flow to startndash Yield value ndash material begins to flow when forces

between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached

ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)

ndash Flocculated particles in suspension are characteristic of plastic flow

22

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

23

Properties of Colloids

ndash Non-Newtonian Flowbull Pseudoplastic Flow

ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth

Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain

molecules begin to align themselves in direction of flow to reduce internal resistance

24

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

25

Properties of Colloids

ndash Non-Newtonian Flowbull Dilatant

ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is

increased with agitationndash Examples include dispersions with gt50 solids of small

deflocculated particles pastes

26

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 6: Lecture 2 - Disperse Systems

6

Basis of Classification

bull In general colloids may be divided into three main groups

bull This division is made on the basis of how the colloidal particles react with the dispersion medium

7

Basis of Classificationndash Lyophilic (or Hydrophilic Colloid)

bull Solvent lovingmdashattraction to dispersion medium (water or alcohol) ndash hydrophilic alcophilic

ndash Natural Polymers (and charge)raquo Acacia (-) Tragacanth (-) Xanthan Gum (-) Protamines

(+)ndash Cellulose Derivatives (and charge)

raquo Methylcellulose (none) Sodium Carboxymethylcellulose (-)ndash Synthetic Polymers (and charge)

raquo PVP (none) Carbomer (-)ndash Particulate Colloids (and charge)

raquo Bentonite (colloidal hydrated aluminum silicate) (-) Veegum (colloidal aluminum magnesium silicate) (-)

8

Basis of Classificationndash Lyophobic (or Hydrophobic Colloid)

bull Low attraction to dispersion mediummdashmust put a lot of energy into system

bull Requires special method to manufacture ndash Particle size reduction or particle condensation by

aggregation

ndash Association Colloidsbull Amphiphilic colloids (polar and nonpolar parts of

molecule)bull Decrease surface tension (surfactants)

9

Preparation of Colloids

bull Hydrophilic colloidal dispersionsndash Spontaneously disperse no special methods

bull Hydrophobic colloidal dispersionsndash Ultrasonic generators

bull gt20000 Hzndash Colloid mills

bull Less efficient broad particle size distribution

10

Colloid Mill

11

Properties of Colloids

bull Kinetic Propertiesndash Brownian movement

bull Random movement of particles in dispersionbull Observed by SEMbull Due to bombardment of small particles by

molecules of dispersion medium

12

Properties of Colloids

bull Optical propertiesndash Tyndall effect ndash light scatteringndash True solution ndash no visible conendash Colloid ndash visible cone due to light scatteringndash Hydrophilic colloids have less pronounced

Tyndall effect than hydrophobic colloids

13Light through mist from ultrasonic nebulizer

14

Light through colloidal dispersion of silver

15

Properties of Colloidsbull Diffusion

ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law

ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across

plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)

ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions

16

Properties of Colloids

bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where

v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium

17

Properties of Colloidsbull Viscosity

ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate

ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx

bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between

platesbull Often plotted dvdx = 1 (FA)

(fluidity)

ndash Unit of viscosity ndash centipoise (cPs)

18

Shearing force required to produce velocity gradient between parallel

plates of a block material

F

dx

A

dv

Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid

19

Properties of Colloids - Flowndash Newtonian Flow

ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples

raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil

20

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

21

Properties of Colloids - Flowndash Non-Newtonian Flow

bull Plastic Flowndash Apparent viscosity decreases with increasing rates of

shearndash Van der Waals attractive forces must be overcome for

flow to startndash Yield value ndash material begins to flow when forces

between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached

ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)

ndash Flocculated particles in suspension are characteristic of plastic flow

22

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

23

Properties of Colloids

ndash Non-Newtonian Flowbull Pseudoplastic Flow

ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth

Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain

molecules begin to align themselves in direction of flow to reduce internal resistance

24

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

25

Properties of Colloids

ndash Non-Newtonian Flowbull Dilatant

ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is

increased with agitationndash Examples include dispersions with gt50 solids of small

deflocculated particles pastes

26

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 7: Lecture 2 - Disperse Systems

7

Basis of Classificationndash Lyophilic (or Hydrophilic Colloid)

bull Solvent lovingmdashattraction to dispersion medium (water or alcohol) ndash hydrophilic alcophilic

ndash Natural Polymers (and charge)raquo Acacia (-) Tragacanth (-) Xanthan Gum (-) Protamines

(+)ndash Cellulose Derivatives (and charge)

raquo Methylcellulose (none) Sodium Carboxymethylcellulose (-)ndash Synthetic Polymers (and charge)

raquo PVP (none) Carbomer (-)ndash Particulate Colloids (and charge)

raquo Bentonite (colloidal hydrated aluminum silicate) (-) Veegum (colloidal aluminum magnesium silicate) (-)

8

Basis of Classificationndash Lyophobic (or Hydrophobic Colloid)

bull Low attraction to dispersion mediummdashmust put a lot of energy into system

bull Requires special method to manufacture ndash Particle size reduction or particle condensation by

aggregation

ndash Association Colloidsbull Amphiphilic colloids (polar and nonpolar parts of

molecule)bull Decrease surface tension (surfactants)

9

Preparation of Colloids

bull Hydrophilic colloidal dispersionsndash Spontaneously disperse no special methods

bull Hydrophobic colloidal dispersionsndash Ultrasonic generators

bull gt20000 Hzndash Colloid mills

bull Less efficient broad particle size distribution

10

Colloid Mill

11

Properties of Colloids

bull Kinetic Propertiesndash Brownian movement

bull Random movement of particles in dispersionbull Observed by SEMbull Due to bombardment of small particles by

molecules of dispersion medium

12

Properties of Colloids

bull Optical propertiesndash Tyndall effect ndash light scatteringndash True solution ndash no visible conendash Colloid ndash visible cone due to light scatteringndash Hydrophilic colloids have less pronounced

Tyndall effect than hydrophobic colloids

13Light through mist from ultrasonic nebulizer

14

Light through colloidal dispersion of silver

15

Properties of Colloidsbull Diffusion

ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law

ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across

plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)

ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions

16

Properties of Colloids

bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where

v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium

17

Properties of Colloidsbull Viscosity

ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate

ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx

bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between

platesbull Often plotted dvdx = 1 (FA)

(fluidity)

ndash Unit of viscosity ndash centipoise (cPs)

18

Shearing force required to produce velocity gradient between parallel

plates of a block material

F

dx

A

dv

Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid

19

Properties of Colloids - Flowndash Newtonian Flow

ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples

raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil

20

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

21

Properties of Colloids - Flowndash Non-Newtonian Flow

bull Plastic Flowndash Apparent viscosity decreases with increasing rates of

shearndash Van der Waals attractive forces must be overcome for

flow to startndash Yield value ndash material begins to flow when forces

between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached

ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)

ndash Flocculated particles in suspension are characteristic of plastic flow

22

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

23

Properties of Colloids

ndash Non-Newtonian Flowbull Pseudoplastic Flow

ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth

Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain

molecules begin to align themselves in direction of flow to reduce internal resistance

24

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

25

Properties of Colloids

ndash Non-Newtonian Flowbull Dilatant

ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is

increased with agitationndash Examples include dispersions with gt50 solids of small

deflocculated particles pastes

26

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 8: Lecture 2 - Disperse Systems

8

Basis of Classificationndash Lyophobic (or Hydrophobic Colloid)

bull Low attraction to dispersion mediummdashmust put a lot of energy into system

bull Requires special method to manufacture ndash Particle size reduction or particle condensation by

aggregation

ndash Association Colloidsbull Amphiphilic colloids (polar and nonpolar parts of

molecule)bull Decrease surface tension (surfactants)

9

Preparation of Colloids

bull Hydrophilic colloidal dispersionsndash Spontaneously disperse no special methods

bull Hydrophobic colloidal dispersionsndash Ultrasonic generators

bull gt20000 Hzndash Colloid mills

bull Less efficient broad particle size distribution

10

Colloid Mill

11

Properties of Colloids

bull Kinetic Propertiesndash Brownian movement

bull Random movement of particles in dispersionbull Observed by SEMbull Due to bombardment of small particles by

molecules of dispersion medium

12

Properties of Colloids

bull Optical propertiesndash Tyndall effect ndash light scatteringndash True solution ndash no visible conendash Colloid ndash visible cone due to light scatteringndash Hydrophilic colloids have less pronounced

Tyndall effect than hydrophobic colloids

13Light through mist from ultrasonic nebulizer

14

Light through colloidal dispersion of silver

15

Properties of Colloidsbull Diffusion

ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law

ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across

plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)

ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions

16

Properties of Colloids

bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where

v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium

17

Properties of Colloidsbull Viscosity

ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate

ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx

bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between

platesbull Often plotted dvdx = 1 (FA)

(fluidity)

ndash Unit of viscosity ndash centipoise (cPs)

18

Shearing force required to produce velocity gradient between parallel

plates of a block material

F

dx

A

dv

Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid

19

Properties of Colloids - Flowndash Newtonian Flow

ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples

raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil

20

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

21

Properties of Colloids - Flowndash Non-Newtonian Flow

bull Plastic Flowndash Apparent viscosity decreases with increasing rates of

shearndash Van der Waals attractive forces must be overcome for

flow to startndash Yield value ndash material begins to flow when forces

between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached

ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)

ndash Flocculated particles in suspension are characteristic of plastic flow

22

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

23

Properties of Colloids

ndash Non-Newtonian Flowbull Pseudoplastic Flow

ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth

Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain

molecules begin to align themselves in direction of flow to reduce internal resistance

24

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

25

Properties of Colloids

ndash Non-Newtonian Flowbull Dilatant

ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is

increased with agitationndash Examples include dispersions with gt50 solids of small

deflocculated particles pastes

26

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 9: Lecture 2 - Disperse Systems

9

Preparation of Colloids

bull Hydrophilic colloidal dispersionsndash Spontaneously disperse no special methods

bull Hydrophobic colloidal dispersionsndash Ultrasonic generators

bull gt20000 Hzndash Colloid mills

bull Less efficient broad particle size distribution

10

Colloid Mill

11

Properties of Colloids

bull Kinetic Propertiesndash Brownian movement

bull Random movement of particles in dispersionbull Observed by SEMbull Due to bombardment of small particles by

molecules of dispersion medium

12

Properties of Colloids

bull Optical propertiesndash Tyndall effect ndash light scatteringndash True solution ndash no visible conendash Colloid ndash visible cone due to light scatteringndash Hydrophilic colloids have less pronounced

Tyndall effect than hydrophobic colloids

13Light through mist from ultrasonic nebulizer

14

Light through colloidal dispersion of silver

15

Properties of Colloidsbull Diffusion

ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law

ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across

plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)

ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions

16

Properties of Colloids

bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where

v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium

17

Properties of Colloidsbull Viscosity

ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate

ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx

bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between

platesbull Often plotted dvdx = 1 (FA)

(fluidity)

ndash Unit of viscosity ndash centipoise (cPs)

18

Shearing force required to produce velocity gradient between parallel

plates of a block material

F

dx

A

dv

Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid

19

Properties of Colloids - Flowndash Newtonian Flow

ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples

raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil

20

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

21

Properties of Colloids - Flowndash Non-Newtonian Flow

bull Plastic Flowndash Apparent viscosity decreases with increasing rates of

shearndash Van der Waals attractive forces must be overcome for

flow to startndash Yield value ndash material begins to flow when forces

between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached

ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)

ndash Flocculated particles in suspension are characteristic of plastic flow

22

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

23

Properties of Colloids

ndash Non-Newtonian Flowbull Pseudoplastic Flow

ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth

Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain

molecules begin to align themselves in direction of flow to reduce internal resistance

24

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

25

Properties of Colloids

ndash Non-Newtonian Flowbull Dilatant

ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is

increased with agitationndash Examples include dispersions with gt50 solids of small

deflocculated particles pastes

26

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 10: Lecture 2 - Disperse Systems

10

Colloid Mill

11

Properties of Colloids

bull Kinetic Propertiesndash Brownian movement

bull Random movement of particles in dispersionbull Observed by SEMbull Due to bombardment of small particles by

molecules of dispersion medium

12

Properties of Colloids

bull Optical propertiesndash Tyndall effect ndash light scatteringndash True solution ndash no visible conendash Colloid ndash visible cone due to light scatteringndash Hydrophilic colloids have less pronounced

Tyndall effect than hydrophobic colloids

13Light through mist from ultrasonic nebulizer

14

Light through colloidal dispersion of silver

15

Properties of Colloidsbull Diffusion

ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law

ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across

plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)

ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions

16

Properties of Colloids

bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where

v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium

17

Properties of Colloidsbull Viscosity

ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate

ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx

bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between

platesbull Often plotted dvdx = 1 (FA)

(fluidity)

ndash Unit of viscosity ndash centipoise (cPs)

18

Shearing force required to produce velocity gradient between parallel

plates of a block material

F

dx

A

dv

Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid

19

Properties of Colloids - Flowndash Newtonian Flow

ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples

raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil

20

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

21

Properties of Colloids - Flowndash Non-Newtonian Flow

bull Plastic Flowndash Apparent viscosity decreases with increasing rates of

shearndash Van der Waals attractive forces must be overcome for

flow to startndash Yield value ndash material begins to flow when forces

between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached

ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)

ndash Flocculated particles in suspension are characteristic of plastic flow

22

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

23

Properties of Colloids

ndash Non-Newtonian Flowbull Pseudoplastic Flow

ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth

Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain

molecules begin to align themselves in direction of flow to reduce internal resistance

24

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

25

Properties of Colloids

ndash Non-Newtonian Flowbull Dilatant

ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is

increased with agitationndash Examples include dispersions with gt50 solids of small

deflocculated particles pastes

26

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 11: Lecture 2 - Disperse Systems

11

Properties of Colloids

bull Kinetic Propertiesndash Brownian movement

bull Random movement of particles in dispersionbull Observed by SEMbull Due to bombardment of small particles by

molecules of dispersion medium

12

Properties of Colloids

bull Optical propertiesndash Tyndall effect ndash light scatteringndash True solution ndash no visible conendash Colloid ndash visible cone due to light scatteringndash Hydrophilic colloids have less pronounced

Tyndall effect than hydrophobic colloids

13Light through mist from ultrasonic nebulizer

14

Light through colloidal dispersion of silver

15

Properties of Colloidsbull Diffusion

ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law

ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across

plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)

ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions

16

Properties of Colloids

bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where

v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium

17

Properties of Colloidsbull Viscosity

ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate

ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx

bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between

platesbull Often plotted dvdx = 1 (FA)

(fluidity)

ndash Unit of viscosity ndash centipoise (cPs)

18

Shearing force required to produce velocity gradient between parallel

plates of a block material

F

dx

A

dv

Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid

19

Properties of Colloids - Flowndash Newtonian Flow

ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples

raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil

20

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

21

Properties of Colloids - Flowndash Non-Newtonian Flow

bull Plastic Flowndash Apparent viscosity decreases with increasing rates of

shearndash Van der Waals attractive forces must be overcome for

flow to startndash Yield value ndash material begins to flow when forces

between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached

ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)

ndash Flocculated particles in suspension are characteristic of plastic flow

22

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

23

Properties of Colloids

ndash Non-Newtonian Flowbull Pseudoplastic Flow

ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth

Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain

molecules begin to align themselves in direction of flow to reduce internal resistance

24

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

25

Properties of Colloids

ndash Non-Newtonian Flowbull Dilatant

ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is

increased with agitationndash Examples include dispersions with gt50 solids of small

deflocculated particles pastes

26

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 12: Lecture 2 - Disperse Systems

12

Properties of Colloids

bull Optical propertiesndash Tyndall effect ndash light scatteringndash True solution ndash no visible conendash Colloid ndash visible cone due to light scatteringndash Hydrophilic colloids have less pronounced

Tyndall effect than hydrophobic colloids

13Light through mist from ultrasonic nebulizer

14

Light through colloidal dispersion of silver

15

Properties of Colloidsbull Diffusion

ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law

ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across

plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)

ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions

16

Properties of Colloids

bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where

v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium

17

Properties of Colloidsbull Viscosity

ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate

ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx

bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between

platesbull Often plotted dvdx = 1 (FA)

(fluidity)

ndash Unit of viscosity ndash centipoise (cPs)

18

Shearing force required to produce velocity gradient between parallel

plates of a block material

F

dx

A

dv

Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid

19

Properties of Colloids - Flowndash Newtonian Flow

ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples

raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil

20

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

21

Properties of Colloids - Flowndash Non-Newtonian Flow

bull Plastic Flowndash Apparent viscosity decreases with increasing rates of

shearndash Van der Waals attractive forces must be overcome for

flow to startndash Yield value ndash material begins to flow when forces

between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached

ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)

ndash Flocculated particles in suspension are characteristic of plastic flow

22

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

23

Properties of Colloids

ndash Non-Newtonian Flowbull Pseudoplastic Flow

ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth

Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain

molecules begin to align themselves in direction of flow to reduce internal resistance

24

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

25

Properties of Colloids

ndash Non-Newtonian Flowbull Dilatant

ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is

increased with agitationndash Examples include dispersions with gt50 solids of small

deflocculated particles pastes

26

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 13: Lecture 2 - Disperse Systems

13Light through mist from ultrasonic nebulizer

14

Light through colloidal dispersion of silver

15

Properties of Colloidsbull Diffusion

ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law

ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across

plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)

ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions

16

Properties of Colloids

bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where

v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium

17

Properties of Colloidsbull Viscosity

ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate

ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx

bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between

platesbull Often plotted dvdx = 1 (FA)

(fluidity)

ndash Unit of viscosity ndash centipoise (cPs)

18

Shearing force required to produce velocity gradient between parallel

plates of a block material

F

dx

A

dv

Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid

19

Properties of Colloids - Flowndash Newtonian Flow

ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples

raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil

20

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

21

Properties of Colloids - Flowndash Non-Newtonian Flow

bull Plastic Flowndash Apparent viscosity decreases with increasing rates of

shearndash Van der Waals attractive forces must be overcome for

flow to startndash Yield value ndash material begins to flow when forces

between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached

ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)

ndash Flocculated particles in suspension are characteristic of plastic flow

22

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

23

Properties of Colloids

ndash Non-Newtonian Flowbull Pseudoplastic Flow

ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth

Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain

molecules begin to align themselves in direction of flow to reduce internal resistance

24

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

25

Properties of Colloids

ndash Non-Newtonian Flowbull Dilatant

ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is

increased with agitationndash Examples include dispersions with gt50 solids of small

deflocculated particles pastes

26

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 14: Lecture 2 - Disperse Systems

14

Light through colloidal dispersion of silver

15

Properties of Colloidsbull Diffusion

ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law

ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across

plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)

ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions

16

Properties of Colloids

bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where

v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium

17

Properties of Colloidsbull Viscosity

ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate

ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx

bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between

platesbull Often plotted dvdx = 1 (FA)

(fluidity)

ndash Unit of viscosity ndash centipoise (cPs)

18

Shearing force required to produce velocity gradient between parallel

plates of a block material

F

dx

A

dv

Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid

19

Properties of Colloids - Flowndash Newtonian Flow

ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples

raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil

20

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

21

Properties of Colloids - Flowndash Non-Newtonian Flow

bull Plastic Flowndash Apparent viscosity decreases with increasing rates of

shearndash Van der Waals attractive forces must be overcome for

flow to startndash Yield value ndash material begins to flow when forces

between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached

ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)

ndash Flocculated particles in suspension are characteristic of plastic flow

22

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

23

Properties of Colloids

ndash Non-Newtonian Flowbull Pseudoplastic Flow

ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth

Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain

molecules begin to align themselves in direction of flow to reduce internal resistance

24

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

25

Properties of Colloids

ndash Non-Newtonian Flowbull Dilatant

ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is

increased with agitationndash Examples include dispersions with gt50 solids of small

deflocculated particles pastes

26

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 15: Lecture 2 - Disperse Systems

15

Properties of Colloidsbull Diffusion

ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law

ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across

plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)

ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions

16

Properties of Colloids

bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where

v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium

17

Properties of Colloidsbull Viscosity

ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate

ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx

bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between

platesbull Often plotted dvdx = 1 (FA)

(fluidity)

ndash Unit of viscosity ndash centipoise (cPs)

18

Shearing force required to produce velocity gradient between parallel

plates of a block material

F

dx

A

dv

Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid

19

Properties of Colloids - Flowndash Newtonian Flow

ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples

raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil

20

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

21

Properties of Colloids - Flowndash Non-Newtonian Flow

bull Plastic Flowndash Apparent viscosity decreases with increasing rates of

shearndash Van der Waals attractive forces must be overcome for

flow to startndash Yield value ndash material begins to flow when forces

between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached

ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)

ndash Flocculated particles in suspension are characteristic of plastic flow

22

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

23

Properties of Colloids

ndash Non-Newtonian Flowbull Pseudoplastic Flow

ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth

Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain

molecules begin to align themselves in direction of flow to reduce internal resistance

24

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

25

Properties of Colloids

ndash Non-Newtonian Flowbull Dilatant

ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is

increased with agitationndash Examples include dispersions with gt50 solids of small

deflocculated particles pastes

26

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 16: Lecture 2 - Disperse Systems

16

Properties of Colloids

bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where

v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium

17

Properties of Colloidsbull Viscosity

ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate

ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx

bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between

platesbull Often plotted dvdx = 1 (FA)

(fluidity)

ndash Unit of viscosity ndash centipoise (cPs)

18

Shearing force required to produce velocity gradient between parallel

plates of a block material

F

dx

A

dv

Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid

19

Properties of Colloids - Flowndash Newtonian Flow

ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples

raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil

20

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

21

Properties of Colloids - Flowndash Non-Newtonian Flow

bull Plastic Flowndash Apparent viscosity decreases with increasing rates of

shearndash Van der Waals attractive forces must be overcome for

flow to startndash Yield value ndash material begins to flow when forces

between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached

ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)

ndash Flocculated particles in suspension are characteristic of plastic flow

22

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

23

Properties of Colloids

ndash Non-Newtonian Flowbull Pseudoplastic Flow

ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth

Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain

molecules begin to align themselves in direction of flow to reduce internal resistance

24

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

25

Properties of Colloids

ndash Non-Newtonian Flowbull Dilatant

ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is

increased with agitationndash Examples include dispersions with gt50 solids of small

deflocculated particles pastes

26

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 17: Lecture 2 - Disperse Systems

17

Properties of Colloidsbull Viscosity

ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate

ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx

bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between

platesbull Often plotted dvdx = 1 (FA)

(fluidity)

ndash Unit of viscosity ndash centipoise (cPs)

18

Shearing force required to produce velocity gradient between parallel

plates of a block material

F

dx

A

dv

Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid

19

Properties of Colloids - Flowndash Newtonian Flow

ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples

raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil

20

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

21

Properties of Colloids - Flowndash Non-Newtonian Flow

bull Plastic Flowndash Apparent viscosity decreases with increasing rates of

shearndash Van der Waals attractive forces must be overcome for

flow to startndash Yield value ndash material begins to flow when forces

between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached

ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)

ndash Flocculated particles in suspension are characteristic of plastic flow

22

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

23

Properties of Colloids

ndash Non-Newtonian Flowbull Pseudoplastic Flow

ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth

Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain

molecules begin to align themselves in direction of flow to reduce internal resistance

24

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

25

Properties of Colloids

ndash Non-Newtonian Flowbull Dilatant

ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is

increased with agitationndash Examples include dispersions with gt50 solids of small

deflocculated particles pastes

26

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 18: Lecture 2 - Disperse Systems

18

Shearing force required to produce velocity gradient between parallel

plates of a block material

F

dx

A

dv

Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid

19

Properties of Colloids - Flowndash Newtonian Flow

ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples

raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil

20

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

21

Properties of Colloids - Flowndash Non-Newtonian Flow

bull Plastic Flowndash Apparent viscosity decreases with increasing rates of

shearndash Van der Waals attractive forces must be overcome for

flow to startndash Yield value ndash material begins to flow when forces

between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached

ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)

ndash Flocculated particles in suspension are characteristic of plastic flow

22

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

23

Properties of Colloids

ndash Non-Newtonian Flowbull Pseudoplastic Flow

ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth

Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain

molecules begin to align themselves in direction of flow to reduce internal resistance

24

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

25

Properties of Colloids

ndash Non-Newtonian Flowbull Dilatant

ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is

increased with agitationndash Examples include dispersions with gt50 solids of small

deflocculated particles pastes

26

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 19: Lecture 2 - Disperse Systems

19

Properties of Colloids - Flowndash Newtonian Flow

ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples

raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil

20

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

21

Properties of Colloids - Flowndash Non-Newtonian Flow

bull Plastic Flowndash Apparent viscosity decreases with increasing rates of

shearndash Van der Waals attractive forces must be overcome for

flow to startndash Yield value ndash material begins to flow when forces

between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached

ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)

ndash Flocculated particles in suspension are characteristic of plastic flow

22

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

23

Properties of Colloids

ndash Non-Newtonian Flowbull Pseudoplastic Flow

ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth

Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain

molecules begin to align themselves in direction of flow to reduce internal resistance

24

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

25

Properties of Colloids

ndash Non-Newtonian Flowbull Dilatant

ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is

increased with agitationndash Examples include dispersions with gt50 solids of small

deflocculated particles pastes

26

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 20: Lecture 2 - Disperse Systems

20

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

21

Properties of Colloids - Flowndash Non-Newtonian Flow

bull Plastic Flowndash Apparent viscosity decreases with increasing rates of

shearndash Van der Waals attractive forces must be overcome for

flow to startndash Yield value ndash material begins to flow when forces

between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached

ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)

ndash Flocculated particles in suspension are characteristic of plastic flow

22

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

23

Properties of Colloids

ndash Non-Newtonian Flowbull Pseudoplastic Flow

ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth

Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain

molecules begin to align themselves in direction of flow to reduce internal resistance

24

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

25

Properties of Colloids

ndash Non-Newtonian Flowbull Dilatant

ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is

increased with agitationndash Examples include dispersions with gt50 solids of small

deflocculated particles pastes

26

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 21: Lecture 2 - Disperse Systems

21

Properties of Colloids - Flowndash Non-Newtonian Flow

bull Plastic Flowndash Apparent viscosity decreases with increasing rates of

shearndash Van der Waals attractive forces must be overcome for

flow to startndash Yield value ndash material begins to flow when forces

between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached

ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)

ndash Flocculated particles in suspension are characteristic of plastic flow

22

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

23

Properties of Colloids

ndash Non-Newtonian Flowbull Pseudoplastic Flow

ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth

Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain

molecules begin to align themselves in direction of flow to reduce internal resistance

24

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

25

Properties of Colloids

ndash Non-Newtonian Flowbull Dilatant

ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is

increased with agitationndash Examples include dispersions with gt50 solids of small

deflocculated particles pastes

26

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 22: Lecture 2 - Disperse Systems

22

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

23

Properties of Colloids

ndash Non-Newtonian Flowbull Pseudoplastic Flow

ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth

Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain

molecules begin to align themselves in direction of flow to reduce internal resistance

24

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

25

Properties of Colloids

ndash Non-Newtonian Flowbull Dilatant

ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is

increased with agitationndash Examples include dispersions with gt50 solids of small

deflocculated particles pastes

26

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 23: Lecture 2 - Disperse Systems

23

Properties of Colloids

ndash Non-Newtonian Flowbull Pseudoplastic Flow

ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth

Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain

molecules begin to align themselves in direction of flow to reduce internal resistance

24

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

25

Properties of Colloids

ndash Non-Newtonian Flowbull Dilatant

ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is

increased with agitationndash Examples include dispersions with gt50 solids of small

deflocculated particles pastes

26

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 24: Lecture 2 - Disperse Systems

24

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

25

Properties of Colloids

ndash Non-Newtonian Flowbull Dilatant

ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is

increased with agitationndash Examples include dispersions with gt50 solids of small

deflocculated particles pastes

26

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 25: Lecture 2 - Disperse Systems

25

Properties of Colloids

ndash Non-Newtonian Flowbull Dilatant

ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is

increased with agitationndash Examples include dispersions with gt50 solids of small

deflocculated particles pastes

26

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 26: Lecture 2 - Disperse Systems

26

FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 27: Lecture 2 - Disperse Systems

27

Properties of Colloidsndash Thixotropy

bull Isothermal and slow recovery on standing of a consistency lost through shearing

bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform

bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is

bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 28: Lecture 2 - Disperse Systems

28

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 29: Lecture 2 - Disperse Systems

29

Approximate Viscosities of Gels at RT (mPa s or cPs)

bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 30: Lecture 2 - Disperse Systems

30

Properties of Colloidsbull Electrical Properties of Colloids

ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles

ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution

ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces

(controlled flocculation)ndash Manipulate zeta potential

bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential

ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in

order to stabilize dispersion

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 31: Lecture 2 - Disperse Systems

31

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 32: Lecture 2 - Disperse Systems

32

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 33: Lecture 2 - Disperse Systems

33

Properties of Colloids

bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize

due to large surface area and large free surface energy particles will flocculate to reduce energy

ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize

ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 34: Lecture 2 - Disperse Systems

34

Suspensions

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 35: Lecture 2 - Disperse Systems

35

Suspensionbull Definition -A heterogeneous system in which the

continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid

bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be

readily dispersible) ndash 3 Product should be viscous enough so patient gets

uniform dose but not so viscous to prevent pouring or injecting

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 36: Lecture 2 - Disperse Systems

36

Pharmaceutical Suspensions

bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase

ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 37: Lecture 2 - Disperse Systems

37

Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes

bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15

mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 38: Lecture 2 - Disperse Systems

38

Stokersquos Law

bullMost important law controlling formulation of suspensionsbullIn equation

ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes

bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 39: Lecture 2 - Disperse Systems

39

Stokersquos Law Applications

bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 40: Lecture 2 - Disperse Systems

40

Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by

2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 41: Lecture 2 - Disperse Systems

41

Methods of Preparation of Suspensions

bull A Dispersion Method -add dispersion medium to finely divided particles

ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and

Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not

remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid

Phenobarbital

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 42: Lecture 2 - Disperse Systems

42

General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free

paste bull 3 Slowly dilute with remainder of vehicle with constant stirring

(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar

with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder

bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming

initial dispersion (same with tinctures) If add before aggregates will form

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 43: Lecture 2 - Disperse Systems

43

Fritsch Planetary Micro Mill

For reducing particle size downTo colloidal size range dry or in suspension

For mixing and homogenizing of emulsions suspensions pastes

Uses grinding balls for high impactenergy

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 44: Lecture 2 - Disperse Systems

44

Methods of Preparation of Suspensions

bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate

(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS

bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)

bull used as astringent (acne) bull 2 Alteration of solvent

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 45: Lecture 2 - Disperse Systems

45

Interfacial Properties of Suspended Particles

bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)

F = SL A

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 46: Lecture 2 - Disperse Systems

46

Interfacial Properties of Suspended Particles

bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse

surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)

--Flocculated particles weakly bonded settle rapidly no cake re-suspend

--Deflocculated particles settle slowly sediment difficult to re-

suspend

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 47: Lecture 2 - Disperse Systems

47

Sedimentation Volumes

bull Sedimentation volumes produced by adding varying amounts of flocculating agent

bull Examples b and c are pharmaceutically acceptable

F = Sedimentation Volume

F = Vu = Final Volume of Susp Sediment

Vo Original Volume of Susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 48: Lecture 2 - Disperse Systems

48

Caking Diagram

bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate

App

aren

t Zet

a Po

tent

ial

F = Sedimentation Volume

F = Vu = Final Volume of susp Sediment

Vo Original Volume of susp

Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)

05

10

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 49: Lecture 2 - Disperse Systems

49

Examples of Official Suspensions

1 Chloramphenicol Palmitate Oral Suspension USP

(Chloromycetin Palmitate Suspension Parke-Davis)

-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract

and chloramphenicol is absorbed -for eye and ear drops derivative not

necessary because acid stability or taste are not problems

USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow

depression)

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 50: Lecture 2 - Disperse Systems

50

Examples of Official Suspensions

bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP

8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)

-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium

hydroxide USE protectant relieves itching sunburn pain poison

ivy 2 Phenolated Calamine Lotion USP

Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes

-must add ldquostink to the zinc in order to obtain fine particles as the precipitate

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 51: Lecture 2 - Disperse Systems

51

Suspending Agents

bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 52: Lecture 2 - Disperse Systems

52

Examples of Suspending Agents

bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol

bull Claysndash Bentonitendash Veegum

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 53: Lecture 2 - Disperse Systems

53

Examples of Suspending Agents

bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 54: Lecture 2 - Disperse Systems

54

Emulsions

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 55: Lecture 2 - Disperse Systems

55

Emulsions

bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 56: Lecture 2 - Disperse Systems

56

Emulsions

bull Termsndash Dispersed PhasemdashVarious droplets

discontinuous phasendash Continuous PhasemdashCarries the dispersed

dropletsndash OW EmulsionmdashOil is the dispersed phase

water the continuous phasendash WO EmulsionmdashWater is the dispersed

phase oil is the continuous phase

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 57: Lecture 2 - Disperse Systems

57

Why Use Emulsionsbull 1 Permits administration of liquid drug in form of

tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally

onto the skin (ie lotion or cream)mdashkeep in friendly environment

bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but

damaged skin to protect (ie Water-proof

sunscreen)OWmdashEasily removed from skin

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 58: Lecture 2 - Disperse Systems

58

To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2

immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between

the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)

--SAA forms a film at interface a prevents coalescence of the droplets

of oil b stabilizes the emulsion

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 59: Lecture 2 - Disperse Systems

59

Nonpolar tail

Interface

Polar head

London dispersion forces

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 60: Lecture 2 - Disperse Systems

60

Emulsions for Internal Use

bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent

(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 61: Lecture 2 - Disperse Systems

61

Emulsions for External Use

bull OW or WO typesbull Use soaps as the emulsifying agents

ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW

ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash

Water insoluble Forms WO

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 62: Lecture 2 - Disperse Systems

62

Stability of Emulsions

bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 63: Lecture 2 - Disperse Systems

63

Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)

- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO

bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)

bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 64: Lecture 2 - Disperse Systems

64

Stability of Emulsions

bull Na Stearate (ow) + CaCl2

bull Ca Stearate (wo)

bull What is the emulsifying agent

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 65: Lecture 2 - Disperse Systems

65

o o

Flocculation

o o

Coalescence

o

w

w

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 66: Lecture 2 - Disperse Systems

66

Preservation of Emulsionsbull Growth of microorganisms cause

--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties

bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential

--ie Methylparaben and Propylparaben

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 67: Lecture 2 - Disperse Systems

67

Emulsion Technologybull Industrial Homogenizers

--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method

Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender

bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 68: Lecture 2 - Disperse Systems

68

High shear homogenizer

Hand homogenizer

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 69: Lecture 2 - Disperse Systems

69

Examples of Official Emulsions

bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing

Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas

Flatulence

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 70: Lecture 2 - Disperse Systems

70

Other Emulsifying Agents

bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)

ndash Sulfonates (R-SO3Na)

bull Cationicndash Quaternary ammonium compounds

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 71: Lecture 2 - Disperse Systems

71

Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)

ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones

bull Low MW have surfactant propertiesbull High MW have antifoaming action

bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 72: Lecture 2 - Disperse Systems

72

Surface Tension and Surfactants

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 73: Lecture 2 - Disperse Systems

73

Surface Tensionbull Surface Tension is the

ndash inward force or stress or tension that tends to pull molecules into the liquid

ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)

bull Surface Tension is the term used when we have an interface of a liquid or solid with air

bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 74: Lecture 2 - Disperse Systems

74

Surface Tension Examplebull Surface tension and interfacial tension

are important considerations in pharmaceutical technology

bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid

bull Molecule A in the interior is completely surrounded by identical molecules

bull These molecules are oriented in such a way that there are no residual forces

bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other

bull With molecule B at the surface the situation is different

bull The molecules in the interior of the liquid tend to pull B into the interior

AB

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 75: Lecture 2 - Disperse Systems

75

Surface Active Agents - Basic Characteristics

bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly

effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-

polar moieties for the molecule to be an effective SAA

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 76: Lecture 2 - Disperse Systems

76

Sodium Lauryl Sulfate

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 77: Lecture 2 - Disperse Systems

77

Interfacial Tension

bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)

bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples

ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 78: Lecture 2 - Disperse Systems

78

Surfactants at the interface

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 79: Lecture 2 - Disperse Systems

79

Schematic of a Surface Active Agent

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 80: Lecture 2 - Disperse Systems

80

Properties of Surfactants

bull Surfactants may be described variously by a number of different titles depending upon how they are used

bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents

bull See Examples of Surfactants Given Earlier

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 81: Lecture 2 - Disperse Systems

81

The HLB Systembull Developed for and is important in surfactant selection

for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both

lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will

determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic

Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is

known as its HLB

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 82: Lecture 2 - Disperse Systems

82

HLB Systembull In general

--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic

bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 83: Lecture 2 - Disperse Systems

83

Solubilizationbull The ability of surfactants to increase the solubility of substances

which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances

which are normally considered to be water insoluble

bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their

ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less

extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a

monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 84: Lecture 2 - Disperse Systems

84

Mechanism of Solubilization cont

bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates

bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form

bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a

spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion

medium

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 85: Lecture 2 - Disperse Systems

85

Schematic of Micelle

Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 86: Lecture 2 - Disperse Systems

86

Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the

micelles begin to form bull The CMC is usually characterized by a distinct change in the

physical properties of the solution bull For example

ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure

bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface

of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady

reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no

further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no

more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 87: Lecture 2 - Disperse Systems

87

Surface Tension and CMC

bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 88: Lecture 2 - Disperse Systems

88

Solubilization

bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like

region it is capable of dissolving oil-soluble substances

bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 89: Lecture 2 - Disperse Systems

89

Applications of Solubilizationbull To improve chemical stability

ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection

by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected

bull To improve drug absorptionndash Improvement orally and through the skin

bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible

mixture that can be added to childrenrsquos formulasbull To reduce irritation

ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 90: Lecture 2 - Disperse Systems

90

Wetting Agent

bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 91: Lecture 2 - Disperse Systems

91

Natural Surfactants

bull In the GI Tractndash Bile salts

bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid

ndash Purpose

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 92: Lecture 2 - Disperse Systems

92

Natural Surfactants

bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 93: Lecture 2 - Disperse Systems

93

Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)

Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH

Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94
Page 94: Lecture 2 - Disperse Systems

94

Natural Surfactants

bull In the Eyendash Cornea ndash Tear Interface

ndash Aqueous Tear Film

ndash Surface of Tear Film

ndash Tear Film

  • Pharmaceutics 356C
  • Disperse or Polyphase Systems
  • Slide 3
  • Slide 4
  • Types of Colloidal Systems
  • Basis of Classification
  • Basis of Classification
  • Slide 8
  • Preparation of Colloids
  • Colloid Mill
  • Properties of Colloids
  • Slide 12
  • Slide 13
  • Slide 14
  • Slide 15
  • Slide 16
  • Slide 17
  • Shearing force required to produce velocity gradient between parallel plates of a block material
  • Properties of Colloids - Flow
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • Slide 28
  • Approximate Viscosities of Gels at RT (mPa s or cPs)
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Suspensions
  • Suspension
  • Pharmaceutical Suspensions
  • Why Use Suspensions
  • Stokersquos Law
  • Stokersquos Law Applications
  • Slide 40
  • Methods of Preparation of Suspensions
  • General Method of Preparation
  • Slide 43
  • Slide 44
  • Interfacial Properties of Suspended Particles
  • Slide 46
  • Sedimentation Volumes
  • Caking Diagram
  • Examples of Official Suspensions
  • Slide 50
  • Suspending Agents
  • Examples of Suspending Agents
  • Slide 53
  • Emulsions
  • Emulsions
  • Slide 56
  • Why Use Emulsions
  • To Maintain a Stable Emulsion
  • Slide 59
  • Emulsions for Internal Use
  • Emulsions for External Use
  • Stability of Emulsions
  • Slide 63
  • Slide 64
  • Slide 65
  • Preservation of Emulsions
  • Emulsion Technology
  • Slide 68
  • Examples of Official Emulsions
  • Other Emulsifying Agents
  • Slide 71
  • Surface Tension and Surfactants
  • Surface Tension
  • Surface Tension Example
  • Surface Active Agents - Basic Characteristics
  • Slide 76
  • Interfacial Tension
  • Surfactants at the interface
  • Schematic of a Surface Active Agent
  • Properties of Surfactants
  • The HLB System
  • HLB System
  • Solubilization
  • Mechanism of Solubilization cont
  • Schematic of Micelle
  • Critical Micelle Concentration
  • Surface Tension and CMC
  • Slide 88
  • Applications of Solubilization
  • Wetting Agent
  • Natural Surfactants
  • Slide 92
  • Slide 93
  • Slide 94