PHARMACEUTICAL DOSAGE FORM

NOTES

T.B.EKNATH BABU

STUDENT AT ARULMIGU

KALASALINGAM COLLEGE OF

PHARMACY

THIS NOTES BASED ON Dr.M.G.R.

UNIVERSITY SYLLABUS

PHARMACEUTICAL AEROSOLS

DEFINITION

A pharmaceutical aerosol is defined as a colloidal system containing liquid and solid particles (active ingredients) suspended

in a propellant (liquefied gas or compressed gas). The power propellants helps in expelling the contents from the container.

Aerosols are meant for topical, systemic and oral administration, these are also known as Pressurized Packages .

Advantages Easy and convenient application. Can be delivered directly to the affected area . Rapid response to the

medicament . Reduced irritation. Dose can be delivered without contamination. Protect unstable drugs. Lower dosage of drug

minimize adverse side effect. Disadvantages Expensive Propellants are toxic in nature. Highly inflammable

Components of Aerosols Propellants Containers Valves and actuators Product concentrate

6 Components of aerosols Propellant Container Valve and actuator Product concentrate container

PROPELLANTS It is responsible for developing the power pressure within the container and also expel the product when the

valve is opened and in the atomization or foam production of the product. Types of propellants (a) Liquefied gases (b)

Compressed gases

(a) LIQUEFIED GASES Dispersing the active ingredient into a fine mist. Pressure within the container remains constant.

Relatively inert and nontoxic. Types of Liquefied gases Chlorofluorohydrocarbons (CFCs) Trichloromonfluoromethane (Prop

11) Dichlorodifluoromethane (Prop 12) Dichlorotetrafluoroethane (Prop 114) Hydrocarbon Propane, Butane, and Isobutane

3.Hydrochlorofluorocarbon and Hydrofluorocarbon Monochlorodifluoroethane , Difluoromethane

(1) Chlorofluorohydrocarbons (CFCs) Propellant of choice for oral and inhalation . Advantages Chemical inertness Lack of

toxicity Non flammability. Disadvantages High cost It depletes the ozone layer Damage global warming potential

(2) Hydrocarbon Can be used for water based aerosols and topical use. Advantages Inexpensive Excellent solvents It does not

cause ozone depletion Disadvantages Inflammable Unknown toxicity produced e.g. propane , butane , isobutane

(3) Hydrochlorofluorocarbon and Hydrofluorocarbon They may not contain chlorine and have one or more hydrogen atom.

These compounds break down in the atmosphere at faster rate than CFCs- lower ozone destroying effect. Advantages Low

inhalation toxicity High chemical stability High purity Not ozone depleting Disadvantages Poor solvent High cost

(b) Compressed gases Used when the aqueous phase need not be miscible with the propellant. Do not have chilling effect, for

topical preparation. Advantages Inexpensive Non flammable No environmental problems Disadvantages Pressure falls during

use Produce coarse droplet spray e.g. CO 2 , N 2 O, N 2

Containers They must be stand at pressure as high as 140 to 180 psig (pounds per sq. inch gauge) at 130 0 F. A . Metals 1.

Tinplated steel (a) Side-seam (three pieces) (b) Two-piece or drawn (c) Tin free steel 2. Aluminium (a) Two-piece (b) One-

piece (extruded or drawn ) 3. Stainless steel B. Glass 1. Uncoated glass 2. Plastic coated glass

Tinplated steel : Used in topical pharmaceutical aerosols Coating decreases the compatibility problems Light Inexpensive

Aluminum: Used in oral aerosols - Metal containers may be further coated with organic coating, e.g. oleoresin, phenolic ,

vinyl or epoxy coating for additional protection .

Glass containers: These containers are preferred because of its esthetic value and absence of incompatibilities. These

containers are limited to the products having a lower pressure and lower percentage of the propellant. Glass is basically

stronger than the metallic containers.

Two types of glass aerosol containers

i) Uncoated glass container: Decreased cost and high clarity and contents can be viewed at all times.

ii) Plastic coated glass containers: These are protected by plastic coating that prevents the glass from shattering in the event

of breakage. Pressures up to 33 psig can be used. Mainly used for some topical and metered dose inhaler aerosols.

Glass Advantage: Absence of incompatibility Its use is limited for products having lower pressure and lower percentage of

propellant There are two types of glass containers: Uncoated glass: Low cost - High clarity Plastic coated glass: Prevent the

glass from shattering in the event of breakage Used for some topical and MDI aerosols

Valves To delivered the drug in desired form. To give proper amount of medication. Not differ from valve to valve of

medication in pharmaceutical preparation . Types - Continuous spray valve - High speed production technique. - Metering

valves

20 Valve components Ferrul or mount cap Valve body or housing Stem Gasket Spring Dip tube Gasket spring

22 Actuator To ensure that aerosol product is delivered in the proper and desired form . These are specially designed buttons

which helps in delivering the drug in desired form i.e., spray, wet stream, foam or solid stream Different types of actuators

Spray actuators Foam actuators Solid steam actuators Special actuators

FORMULATION

Depending on the type of aerosol system utilized, the pharmaceutical aerosol may be dispensed as fine mist, wet spray,

quick-breaking foam, stable foam, semi solid or solid. The type of system selected depends on i) physical, chemical and

pharmacological properties of active ingredients ii) site of application An aerosol formulation consists of two components: i)

Product concentrate ii) Propellant

i) Product concentrate: consists of active ingredients or a mixture of active ingredients and other agents such as solvents,

antioxidants and surfactants.

ii) Propellant: .single or blend of propellants may be used. The propellant is selected to give the desired vapor pressure,

solubility and particle size. Fluorinated hydrocarbons are gases at room temperature. They may be liquefied by cooling their

boiling point or by compression at room temperature. Eg : Freon 12 will form a liquid when cooled to -30° C(-22° F) or when

compressed to 70 psig at 21°C(70° F). Blend of solvents is used to achieve the desired solubility.

Surfactants are mixed to give the proper HLB value for an emulsion system. Space aerosols usually operate at 30 to 40 psig at

21° C and may contain as much as 85% propellant. Surface aerosols commonly contain 30 to 70% propellant with pressures

between 25 and 55 psig at 21°C(70° F). Foam aerosols usually contain only 6 to 10 % propellant and operate between 35 and

55 psig at 21°C (70° F). These aerosols can be considered to be emulsions.

Types of system Solution system Water based system Suspension or Dispersion systems Foam systems 1. Aqueous stable

foams 2. Nonaqueous stable foams 3. Quick-breaking foams 4. Thermal foams Intranasal aerosols

Types of systems

1. Solution system •Consist of two phases liquid and vapor •If the active ingredient is soluble in propellant it has one system

•The ratio of propellant and solvent could range from 5% (foaming) to 95% (inhalation). •To lower vapor pressure we can add

solvents of non volatile e.g. Propylene glycol, acetone, alcohol

2. Water based systems •Are increasing in use nowadays •Have relatively large amount of water •There is three phase system:

water, propellant and vapor. •In aquasol system it has two phases i.e. water and vapor

3. Dispersed systems (suspension) •It needs surfactants •Particle size is important

4. Foam systems •Have foaming agent •Aqueous or non aqueous

MANUFACTURING PROCEDURE FOR AEROSOLS

1. Pressure filling

2. Cold filling

3. Compressed gas filling

Equipments used Those fill at pressurized and low temperature 1. Pressure filling (gauge-burette) 2. Cold filling (low temp.)

3. Compressed gas filling (after concentrate has been filled)

Pressure filling apparatus

It consists of a pressure burette which helps in metered filling of liquefied gas in to the aerosol container under pressure, an

inlet valve is present at the bottom or top of the pressure burette, which incorporates the propellant into the container and

flows with its own vapour pressure in the container. The trapped air escapes out from the top valve. The propellant which are

having low pressure stop flowing as the pressure of burette and container becomes equal. If further propellant is to be added,

then the aerosol container is attached to the container is attached to the nitrogen cylinder through a hose(rubber pipe), the

pressure exerted by nitrogen helps in the flow of the propellant into the container. Otherwise compressed air is provided on

the upper wall of the container for further addition of propellant. another device which consists of piston arrangement can also

be used for pressure filling. This device helps in always maintaining positive pressure. This type of device cannot be used for

filling inhalation aerosols which have metered valves.

PROCEDURE: It is a slow method compared to cold filling method. But with the latest developments, the production rate has

been greatly increased. This method involves filling of the concentrate into the container at the room temperature. Then the

valve is placed in the container and crimped. Through the opening of the valve the propellant are added or it can be added

“under the cap”.

Since the opening of the valve are smaller in size ranging from 0.018-0.030 inches, it limits the production and the process

becomes slow. But with the use of rotary filling machines and new filling heads where the propellants are filled through valve

stem, the production rate is increased. The trapped air in the container and air present in head space is removed before filling

the propellant. This is done so as to protect the products from getting adversely affected.

ADVANTAGES: Solutions, emulsions, suspensions can be filled by this method as chilling does not occur. Contamination

due to moisture is less. The production rate can be increased. Loss of propellant is less.

Various units used in pressure filling methods are, Air cleaner Concentrate filler Valve placer Propellant filler Valve crimper

Water bath Labeler Coder Packing table Vacuum crimper Pressure filler The fillers does not have the facility of refrigeration

as chilling is not required. vacuum crimper and pressure filler comes under single unit if filling is carried by ‘under the cap’

method.

Cold filling apparatus

The apparatus used for cold filling purpose is simpler compared to pressure filling apparatus. It consist of an insulated box in

which copper tubings are placed. The tubings are coiled to increase the area for cooling. Before operating the nit, the insulated

box should be filled with dry ice or acetone. The apparatus can be operated with or without metered valves. Hydrocarbon

propellant cannot be filled into aerosol containers using this apparatus because large amount of propellant escapes out and

vaporizes. This may lead to formation of an explosive mixture at the floor level. Fluorocarbons do not form any explosive

mixture although their vapours are heavier than air.

PROCEDURE: non aqueous products and products which can withstand low temperature that is -40ºF are used in this

method. The product concentrate are chilled to a temperature of -40ºF and filled into already chilled container. Then the

chilled propellant is added completely in 1-2 stages. The filling of propellant depends upon the amount of propellant is used.

Another method is to chill both the product concentrate and propellant in a separate pressure vessel and then filling them into

the container. The valve is placed and crimped on the container. Then test for leakage and strength of container is carried out

by passing container into a heated water bath, where the contents of the container get heated to 130ºF. After this, they are air

dried, and the caps are placed on the container and labeled.

The cold filling method is no longer being used, as it has been replaced by pressure filling method. Various units used in

pressure filling methods are, Air cleaner Concentrate filler Valve placer Propellant filler Valve crimper Water bath Labeler

Coder Packing table the fillers are capable of refrigeration since the product concentrate and propellant are chilled.

Compressed gas filling apparatus

The filling of compressed gas does not require any large equipments and can be easily done in the lab. To reduce the pressure

of compressed gas (high pressure), a pressure reducing valve is required. The apparatus consists of delivery guage. A flexible

hose pipe which can withstand high guage pressure that is 150 pounds per square inch is attached to the delivery guage along

with the filling head. A flow indicator is also present in specialized equipments.

PROCEDURE: The product concentrate is filled into the container. Valve is placed and crimped on the container. With the

help of vacuum pump the air is removed from the container. Filling head is put in the opening of the valve and the gas is

allowed to pass. The gas stops flowing if the delivery pressure and the pressure within the container become equal. Carbon

dioxide and nitrous oxide is used if more amount of gas is required or for the stability purposes. High solubility can be

achieved by shaking the container manually or with the help of mechanical shakers.

PHARMACEUTICAL APLLICATION

1. Aerosols are those preparations containing therapeutically active ingredients which either dissolved or suspended in the

propellant blends and solvents. The propellants are in the form of compressed gases and liquefied gases. Aerosols are used for

oral or topical administration.

2. Aerosols exhibits local action in nose, throat, lungs, eye, ear, vagina or rectum.

3. Aerosols also exhibit systemic effect when they pass from the lungs and get absorbed into the blood stream. 4. Metered

dose inhalers help in administration of the liquid or solid mist or spray to the respiratory system or to the nasal passage.

5. The particle size should be below 10µm. For effective or maximum therapeutic activity, particle size should range between

3-6 µm,

6. Aerosols are used to formulate several agents which includes local analgesics, antiseptics, fungicides, antibiotics and anti-

inflammatory agents.

7. Aerosols are available in non pharmaceutical preparations like deodorants, perfumes, cosmetic air sprays, toothpastes and

shaving creams .

8.They are also available as house hold products such as spray starch, waxes, polishes, cleaners and lubricants. 9. The drug

administered through aerosols gives quick response and rapid action. As aerosol containers are fitted with metered valves.

10. These preparations are easy to carry.

11. They are uniformly applied without touching the affected area.

12. Sterility of the product is maintained during storage even after opening the valve(as micro organisms cannot enter the

container).

13. The drug does not undergo hydrolysis as there is no water present in the propellant.

14. The drugs are well protected from light and air in aerosol formulation.

15. Patient compliance is high.

Evaluation Of Pharmaceutical Aerosol

A . Flammability and combustibility Flash point Flame extension, including flashback B. Physiochemical characteristics .

Vapor pressure Density Moisture content Identification of propellant(s) Concentrate-propellant ratio C. Performance 1.

Aerosol valve discharge rate Spray pattern Dosage with metered valves Net contents Foam stability Particle size

determination Leakage Biologic characteristics E. Therapeutic activity Evaluation parameters of pharmaceutical aerosols

Flammability and combustibility i) Flash point: It is mainly determined by the use of standard tag open cup apparatus.

Aerosol product is chilled to a temperature of about -25° F and transferred to the test apparatus. The test liquid is allowed to

increase slowly in temperature, and the temperature at which the vapors ignite is taken as the flash point. The flash point

obtained is usually the flash point of the most flammable component (hydrocarbon propellant in case of topical aerosols).

ii) Flame extension or flame projection: This test indicates the effect of an aerosol formulation on the extension of an open

flame. The product is sprayed for about 4 sec into the flame. Depending on the nature of the formulation, flame is extended,

the exact length is measured with a ruler.

B. Physicochemical characteristics: i) Vapor pressure: The pressure can be measured with a pressure gauge or through the use

of a water bath and test gauges. Excessive pressure variation from container to container indicates the presence of air in the

head space. A can puncturing device is available for accurately measuring vapor pressure.

ii) Density: Hydrometer or pycnometer is mainly used to determine the density of an aerosol system. A pressure tube is fitted

with metal flanges and a Holk valve, which allows for the introduction of liquids under pressure. The hydrometer is placed

into the pressure tube. Sufficient sample is introduced the valve to cause the hydrometer to rise halfway up the length of the

tube and the density can be read directly. Specific gravity can be determined through the use of high pressure 500 mL

cylinder.

iii) Moisture: Presence of moisture can be determined by using a) Karl Fischer b) Gas Chromatography

iv) Identification of propellants: Identification of propellants and composition of each propellant in the blend can be done by

using a) Gas chromatography b) Infrared spectrometry

C) Performance: i) Aerosol valve discharge rate: Known weight of an aerosol product has been taken and discharging the

contents for a given period of time using standard apparatus. The container is reweighed after the specified time, the change in

the weight per time gives the discharge rate, expressed as grams per second .

ii) Spray patterns: The method is based on the impingement of the spray on a piece of paper that has been treated with a dye-

talc mixture. An oil soluble or water soluble dye is used depending on the nature of the aerosol. The particles that strike the

paper cause the dye to go into the solution and to be absorbed onto the paper. This gives a record of the spray, which can be

used for the comparison purposes. To control the amount of material coming into contact with the paper, the paper is attached

to a rotating disk that has an adjustable slit.

iii) Dosage with metered valves: Reproducibility of the dose was observed when the valve is pressed. Actual amount of

medication received by the patient. Reproducibility of the dosage may be determined by assay techniques whereby one or two

doses are dispensed into a solvent or onto a material that absorb the active ingredient. These solutions can be assayed and the

amount of active ingredients determined. Another method involves accurate weighing of the filled container followed by

dispensing of several doses. The container can be reweighed and the difference in weight divided by the number of doses

dispensed gives the average dose. This test can be repeated and compared the results. Determination of dose received by a

patient is rather difficult procedure, since all of the material dispensed is not carried to the respiratory tract.

iv) Net contents: The tared cans that have been placed onto the filling line are reweighed and the difference in weight is equals

to the net contents. Destructive method: weighing of full container followed by dispensing of the contents from the container.

The contents are then weighed, with provision being made for the amount retained in the container. Other method is opening

the container and removing as much of the product as possible. This test mainly useful for determining the actual amount that

can be dispended. Weight of empty container =W1 gm Weight of the filled container = W2gm Difference in the weight = W1-

W2gm net content. Distractive method: weight the filled container, dispensing the content and than contents are weigh.

v) Foam stability: The life of foam can range from a few seconds to one hour or more depending on the formulation. Methods

include: i) visual evaluation ii) time for a given mass to penetrate the foam iii) time for a given rod that is inserted into the

foam to fall iv) use of rotational viscometers.

vi) Particle size determination: Two methods are used to determine the particle size of the aerosols. 1) Cascade impactor 2)

Light scattering decay

1) Cascade impactor: This method analyses the particles having diameters ranging from 0.1 to 30μ. A series of nozzles and

glass slides at high velocity are projected through a stream of particles, the larger particles become impacted first on the lower

velocity stages. the smaller particles pass on and are collected at higher velocity stages

2) Light scattering decay: Determination of particle size in epinephrine aerosols. The aerosol settles under turbulent

conditions, the change in light intensity of a Tyndall beam is measured. It is noted that a) a mass median diameter of an

epinephrine aerosol ranged from 2.7 to 3.5 μ b) 70% to 78% of the particles were less than 5μ c) 88% to 93% were less than

7μ d) 98% to 100% were less than 10μ

D) Biological testing: This type of testing an aerosol should include a consideration of therapeutic activity and toxicity.

Therapeutic activity: the dosage of the product has to be determined for inhalation aerosols and this must be related to the

particle size distribution. Topical preparations are applied to the test areas and adsorption of the therapeutic ingredients can be

determined Toxicity: Aerosol applied topically may be irritating to the affected area and or may cause chilling effect. When

the skin is sprayed with an aerosol for a given period of time, the change in the skin temperature was observed .this change in

temperature is mainly determined by the use of thermistor probes attached to recording thermometers. Inhalation toxicity can

also be determined by exposing the test animals to vapors sprayed from an aerosol container.

SUPPOSITORY

All types of suppositories are melt at normal body temperature after introducing in body cavity and produce their effect. Page

2 It is comes under semi solid preparation because it is prepared by melting all ingredients (bases and other additives along

with active ingredient). It is solid dosage form meant to be inserted into Body cavity like rectum , urethra, vagina, where

they melt or soften to release the drugs and produce their local or systemic effect.

ADVANTANGE OF SUPPOSITORY

It is suitable for the drugs which are destroyed by portal circulation. It is suitable for infants and old people who find difficulty

in swallowing of drugs. It is suitable for drugs which produce irritating effect in GIT. It is suitable for unconscious patients

which can not taken drugs orally. Drugs having bad odour and taste can be used in suppository form. It is the alternated

dosage form for drugs which have less bioavailability when it is taken orally.

DISADVANTAGE OF SUPPOSITORY

Leakage problem is also most critical problem along with suppository after introducing in body cavity at elevated

temperature. Page 4 The most important problem is storage condition because it stored at low temp. (10-20 0c ). Other than

the bases get liquefied. The drugs which cause irritation to mucous membrane can not be administrated by this form. The

manufacturing process is more difficult as compare other formulation. The shape of suppository used in rectal is torpedo

shape TYPES OF SUPPOSITORY

(A)RECTAL SUPPOSITORY-

. The length is about 3 Page 5 cm. The weight of suppository used in children is about 1g and in adult about 2g. It is

inserted in the rectal .

(B) URETHRAL SUPPOSITORY

It is available in pencil shape. Those intended for males weigh 4 gm each and are 100-150 mm long. The weight of this type

suppository is about 2g and 60-75 mm long in Females.

(C) VAGINAL SUPPOSITORY

It is contains the combination of polyethylene glycol of different molecular weights as suppository bases. Page 7 It is

contains the drugs which are used in treatment of the infections of female genitourinary tract and meant for contraception. It

is about 3-5g in weight. It is in oviform shape.

(D) NASAL SUPPOSITORY

It is about 1g in weight. It is cylindrical in shape. These are meant for introduction into the ear. It is also known as

AURINARIES. The glycero- gelatin is used as suppository bases. (E) EAR CONE It is about 1g in weight. These

suppository are meant for introduction into nasal cavity

FORMULATION OF SUPPOSITORIES (

A) SUPPOSITORIES BASES-

B) IDEAL PROPERTIES OF SUPPOSITRIES BASES- The following properties should be required for bases---

IDEAL PROPERTIES OF SUPPOSITRY BASES

It should retain hardness and It should be stable during storage condition , No change in colour, shape , odour It should not

irritate and produced inflamed sensation in body cavity. Bases should be exist in solid form at room temperature. It should

have sponification no. range between200-245. It should have iodine value less than 7. It should have acid value less than

0.2 or zero. It should have good emulsifying and wetting property. It should not reacts with drugs and additives.

(1) HYDROPHILIC BASES(A) WATER DISPERSIBLE BASES-

Cellulose derivatives like methylcellulose, sod.carboxymethyl cellulose are also comes under this class. Page 12 These

are used alone or in combination with other type of bases. These are the mixture of non ionic surfactants which are

chemically related to polyethylene glycol.12. This types of bases are interact with few drugs and alter the

bioavailability of these drugs. Page 13 They can be stored at elevated temperature. Disadvantages- They do not

support the growth of microbes in the preparation. They are suitable for both water soluble and oil soluble drugs.13.

Advantages

EXAMPLES

Combination of Tween 61 (85%) and glyceryl monostearate (15%) Page 14 Combination of Tween 61(60%) and Tween

60(40%) Sorbitan fatty acid esters(SPANS) Polyoxyethelene stearates(MYRIS) Polyoxyethylene sorbitan fatty acid

ester(TWEENS)

(B) WATER SOLUBLE BASES (1) GLYCERO-GELATIN- For gets a stiff mass , the quantity of gelatin should be increased

to 32.5% and reduced the glycerol to 40%. Page 15 According to BP the composition of the bases – GELATIN- 14% w/w

GLYCEROL– 70% w/w WATER– QS It is a mixture of gelatin, glycerol, and water. This occurs as a gels

16. PREPARATION OF GLYCERO-GELATINE BASES GLYCEROL WATER GELATINE GLYCERO-GELATINE

BASES

ADVANTAGES

It absorbs moisture and promotes microbial growth , so this reason preservatives are used . Page 17 This base is disperse

slowly in the body cavity fluids and provides prolonged release and action of drugs. DISADVANTAGES- Suppository

prepared by glycero-gelatin bases are strong and translucent unlike cocoa butter suppositories.17.

DISADVANTAGES

Handling and manufacturing of these type of suppository are difficult. Page 18 It requires special storage condition at about

10-15 0c. It exerts undesirable laxative action. It causes dehydration and irritation of rectal mucosa The bases are show

incompatibility with protiens prescipitants due to the gelatin18.

. (2) POLY ETHYLENE GLYCOL(POLYGLYCOL)

They are the mixture of two or more grades of macrogols used as suppository bases. Page 19 They are also called as

macrogols. Solid have mol.weight about more than 1000. Liquids have mol.weight about 200-600. They occur in

liquid and solids. They are long chain polymers of ethylene oxide. CARBOWAXES(U.S) It is also called as

PASTONALS (GERMANY). 19

FOR SOFT SUPPOSITORY PEG 1000- 96 parts PEG 4000- 4 parts Page 20 FOR HARD SUPPOSITORY PEG 1000- 75

parts PEG 4000- 25 parts PEG 4000- 33 parts PEG 6000- 47 parts PURIFIED WATER- 20 parts20. EXAMPLES

ADVANTAGES

It is chemically stable. Page 21 It has good water absorbing capacity. It dose not move out from body cavity after

introducing. It does not support microbial growth. It does not get degraded or hydrolysed. This base is thermostable.21.

DISADVANTAGES

Sometimes leakage may be occur after introducing in body cavity. Page 22 The physical characteristics of the bases are

change from batch to batch. Large quantities of water can not be incorporated into the bases.So emulsifier such as tween 61

(6-10%) are useful to increase the absorption of water. It melt easily in warm weather,so it should stored in cool place in

warm season. It is susceptible to rancidification,so it should be stored in dry place away from light.22.

. (2) LIPOPHILIC BASES (a) COCOA BUTTER

It consists of a mixture of ester of oleic acid,palmatic acid,stearic acid and other fatty acid with glycerol. Page 23 At room

temperature ,it is yellowish- white with a paints,chocolate like odour. It can exist in more than one crystalline form or

exhibits polymorphism. Among all fatty acid about 40% are unsaturated fatty acid . It is natural triglyceride.23

ADVANTAGES

It does not cause irritation in mucous membrane. Page 24 It shows good release of water soluble drugs. It has emollient

effect which is useful to relieve inflammation. It is liquified readily on warming and sets rapidly on cooling.24.

DISADVANTAGES

Sometimes leakage may be occur. Page 25 It required extra lubricant during poring in holder. The physical property of the

base is vary from batch to batch. It gives soft suppository when formulated along with chloral hydrate , phenol, volatile oil,

which have lower melting point. It is susceptible to rancidification ,so it should be stored in dry place away from light.25.

(B) ANTI OXIDANTS

Tocopherol Page 26 Hydroquinone Butylated hydroxy toluene (BHT) Butylated hydroxy anisole (BHA) Ascorbic

acid Ethyl or propyl gallate These are commonly used in all types of suppositories. EXAMPLES- It is protect the drugs

and bases from getting degraded due to oxidation.26.

(C) EMULSIFYING AGENTS

Wool fats Page 27 Wool alcohol Poly sorbates (TWEEN 61) EXAMPLES These are increase the water absorbing

capacity of fatty bases.27.

(D) HARDENING AGENTS

Macrogols at high molecular weight. Page 28 Beeswax EXAMPLES These are the agents which are used to bring the

melting point to normal. These are involved in those formulation where the melting point of the bases is decrease by the

drugs.28.

PRESERVATIVES

Propyl paraben Page 29 Methyl paraben Chorocresol EXAMPLES These are the agents which are used in prevent the

growth of microbial in suppository which contains water soluble bases.

. (F) THICKENING AGENTS

Steary alcohol Page 30 Magnisium stearate Colloidal silica Aluminium monostearate EXAMPLES These are the

agents which are used to increases the viscosity of molten bases and prevent sedimentation of suspended in solid bases.

. (G) PLASTICIZERS

Tween 85 Page 31 Tween 80 Glycol Glycerine Castor oils EXAMPLES It is also used to make the less brittles to

suppositories. These are the agent which are used to improved flexibility of suppositories.

Molds have different capacities like 1,2,4,8gm. Page 32 In side the molds the cavities are made up of aluminium , brass,

stainless steel , plastics. It is consists of two or more parts which are joined with a screw. Molds used in preparation of

suppositories are the metals devised with different shape.

METHODS OF PREPARATION OF SUPPOSITORIES MOLDS USED IN PREPARATION OF SUPPOSITORIES-

34. PLASTICS MOLDS Page 34

CALIBRATION OF THE MOLDSCC

To determine the volume of the mold, the suppositories are melted in a calibrated beaker, and the volume of the melt is

determined. Page 35 The suppositorys combined and average weight is recorded. The first step is to prepare molded

suppositories from base material alone.35.

LUBRICANTS USED IN MOLDS

The nature of lubricants should be different from nature of bases. Page 36 The lubricants are form a film between the wall

of mold cavity and base of suppositories so it prevent adhering of bases to the molds. It is also useful in easy removal of

suppositories from the molds. This is prevent sticking of bases to the wall of molds cavity. Cocoa butter and glycero-

gelatine bases are required lubrication of molds.36.

37. EXAMPLES(1) FOR COCOA BUTTER BASES ALCOHOL(90%)- 50ml GLYCEROL - 10ml SOFT SOAP - 10 gm(2)

LIQUID PARAFFIN(3) ARACHIS OILS

MANUFACTURING OF SUPPOSITORIES

It is more time consuming and not uniformity process. Page 38 It is more economical methods. It is suitable for thermo

labile drugs. Hand molding is useful when we are preparing a small number of suppositories. Heat Molding 1) HAND

MOLDING- Compression Molding Automatics Machine Molding Hand molding

The39. STEPS INVOLVED IN HAND MOLDING Then cut the rods and made one end to Page 39 pointed. Then these

masses are rolled into the shape of a cylindrical rod on the rolling tile in presence of lubricants to prevent the adherence of

masses. It is incorporated into the suppository base by kneading with it or by trituration in a mortar. drugs and other

additives are made into a fine powder .

40. DRUG+ADDITIVES FINE POWDER MIXED IN BASES APPLY LUBRICANTS ON ROLLING TILE ABOVE

MASSES ARE ROOLED IN CYLINDRICAL SHAPE CUT THE RODS PACKED STORED

In this ,if any mass deposited in mold is not removed during cleaning, so produce overweight suppositories with mold marks.

Page 41 In this ,there are no chance of air entrapment and contamination of suppositories. By this the rate of production of

suppositories is more higher than hand molding. Using this machine, up to about 10,000 suppositories per hour can be

produced. All the operations in pour molding are done by automatic machines.41. (2) AUTOMATIC MACHINE

MOLDING

The cooling system results the solidification of suppositories. Page 42 The excess mass is removed by the scraping unit.

Before mass filled in mold ,the lubricant are apply in mold wall. This table rotates sequentially, the mold gets filled with

drug , additives, bases and cooled and ejects the suppositories. This machine consists of a turn table in which metal molds

are fitted. The rate of production of suppositories are about 3500-6000/hr.42. There are two types of machines used they

are following---(a)Rotary Machine-

STEPS INVOLVED IN PROCESS AS FOLLOWING Page 43 Then completed the ejection process , the empty molds are

again moves towards the filling unit for further processes. After the cooling the mold is moves towards ejection station , it

consists of a stainless steel rod which push out the suppositories from molds.43.

44. DRUG+ADDITIVES FINE POWDER MELT BASES + POWER HOPPER LUBRICATED THE MOLDS FILL

ABOVE MIXTURE IN MOLD COOLING SYSTEM EJECTION SYSTEMPACKED STORED

The rate of production is higher than rotary machine. Page 45 There is no chance of air entrapment and contamination of

suppositories as similar to rotary machine. All steps involved is similar to rotary machine. Except the rate of production is

more higher than rotary machine about 10000/hr. It is similar to rotary machine.45. (b) LINEAR MACHINE

COMPRESSION MOLDING

After cooling release them from compression machine and packed . Page 46 Then mass fulfill in mold move and s remove

the suppositories and keep them in cool placed. WORKING- When placed the mass in cylinder and apply the pressure .

CONSTRUCTION- The compression machine consists of a cylinder, piston , molds, and a metallic stop plate at the bottom.

47. PROCEDUREDRUG+ADDITIVES FINE POWDER MIXED WITH BASES LUBRICANTS APPLY IN MOLDS

PLACED THE MASSES IN CYLINDER APPLY PRESSURE RELEASE SUPPOSITORYCOOLED PACKED STORED

. ADVANTAGE-

The main disadvantage is air entrapment occurs during production so oxidation takes place in suppository. Page 48

DISADVANTAGE- Rate of production is more. It is suitable for thermolabile drugs because in this method no heat is

required48.

HEAT MOLDING

The following methods are involved in this process-(a)Melting the bases(b)Incorporation of the drugs and other

additives(c)Filling of mold(d)Cooling and collection of suppositories Page 49 In this process the bases are melted and the

drugs , additives are mixed in bases. These above liquid are mixed in melted bases in half amount after mixing , then added

remaining liquid in bases. Page 50 Triturate the ingredient on warm tile with the sufficient water. the drugs and additives

are in solid form , they are converted in fine powder and mixed properly on a warm tile. Incorporation of drug and additives

FILLING OF MOLDS

Overfilling is required to prevent the depression in suppositories. Page 51 During introducing the masses in molds the

stirring should be done to prevent the sedimentation of insoluble solids , if they present. Then the above masses are

introducing in molds. First the lubricants are apply in molds.

COOLING AND COLLECTION OF SUPPOSITORIES

Then open the mold and collect the suppositories and packed. Page 52 Cool the suppositories for 10-15 min. in

refrigerators. After the2-3 min . the mass just sets. Then remove the excess mass with warm spatula.

MELTING THE BASES DRUGS FINE POWDER TRITURATE WITH WARM WATER LIQUIDS MIXED ½ PARTS OF

LIQUIDS MIXING PROPER

APPLY THE LUBRICANTS IN MOLD OVERFILLING OF MASSESIN MOLDS REMOVE THE EXTRA MASSES

COOLING (10-15MIN) OPEN MOLDS PACKED STORED

. PACKING OF SUPPOSITORIES (1) DISPOSABLE MOLDS- These are meant for packing the suppositories. These are

made of plastics or aluminium foil. 56. (2) MODERN PACKING MACHINE It is consist of roll of packing materialwhich cut

in the required size and rolled around each suppositories. STORAGE CONDITION

The suppositories with cocoa butter stored at Used air tight container It is stored at 10-15 0c57. • < The suppositories

with glycero-gelatin stored at30 0c. < 35 0c.

TEST/EVALUATION OF SUPPOSITORIES.

a) Melting Range test :-

a) Melting Range test :- This test is also called the macro melting range test and is a measure of the time it takes for the entire

suppository to melt when immersed in a constant- temperature water bath. In contrast the micro melting range test is the

melting range measured in capillary tubes for the fat base only. The apparatus commonly used for measuring the melting

range of the entire suppository is a USP Tablet Disintegration Apparatus.

b) Liquefaction or Softening time test:- :

This test consists of a U-tube partially submersed in a constant- temperature water bath. A constriction on one side holds the

suppository in place in the tube. A glass rod is placed on top of the suppository, and the time for the rod to pass through the

constriction is recorded as the “softening time”. b) Liquefaction or Softening time test:-

c) Breaking Test:- :

c) Breaking Test:- The breaking test is designed as a method for measuring the fragility or brittleness of suppositories. The

apparatus used for a test consists of a double-wall chamber in which the test suppository is placed. Water at 37’C is pumped

through the double walls of the chamber, and the suppository, contained in the dry inner chamber, supports a disc to which a

rod is attached. The other end of the rod consists of another disc to which weights are applied. The test is conducted by

placing 600 g on the platform. At 1-min intervals, 200 g weights are added, and the weight at which the suppository collapses

is the breaking time.

d) Dissolution Test:- :

Testing for the rate of in vitro release of drug substances from suppositories has always posed a difficult problem, owing to

melting, deformation, and dispersion in the dissolution medium. Early testing was carried out by simple placement in a beaker

containing a medium. In an effort to control the variation in mass/ medium interface, various means have been employed

including a wire mesh basket, or a membrane, to separate the sample chamber from the reservoir. Samples sealed in dialysis

tubing or natural membrane have also been studied. Flow cell apparatus have been used, holding the sample in place with

cotton, wire screening, and most recently with glass beads.

Displacement value:- The volume of suppository from particular mold is uniform but its weight will vary because the density

of medicament usually differ from the density of base . To prepare product accurately , allowance must be made for the

change in density of mass due to added medicament The most convenient way of making this allowance is to use the

displacement value-“ the number of part by the weight of medicament that displace the one part by weight of base”

What is packaging ? It is the art and science of preparing articles for transport, storage, display and use. It is the process by

which the pharmaceuticals are suitably placed so that they should retain their therapeutic effectiveness from time to time of

their packaging till they are consumed.

Objectives of Packaging:

Objectives of Packaging Presentation Identification, information Protection Convenience, compliance Containment during

storage. Preserves integrity of product

Pack design:

Pack design Proprietary name Dose Approved names of API Uses Usage instructions Actual design may vary . company

identity should be retained . Prescription drugs - straight forward design OTC drugs – Distinctive design

Functions of pack:

Functions of pack Environmental protection : TEMPERATURE: High temp - ⬆ rate of reaction - ⬇ shelf life Repeated cycling

of temp – stability problems. Ex: cracking of creams LIGHT: UV light causes photo degradation. Remedy: colored/ opaque

containers, secondary packs.

MOISTURE AND HUMIDITY: Presence of water – hydrolysis and microbial growth → chemical instability High humidity

→ physical problems. Ex: caking of powders, Remedy: silica gel desiccants VOLATILE Materials O2 i → oxidation . Co 2 -

dissolve in water → carbonic acid → ↓ pH of product

Mechanical protection: Transportation & storage - mechanical stress to product. ∴ secondary packaging COMPRESSION:

Packs are stacked upon each other - crushed. → affects appearance & saleability. Remedy: secondary packs made of

cardboards of suitable thickness.

IMPACT: Movement / accident - sudden & intense forces. Remedy: Cushioning primary pack, Hold primary pack snugly in

secondary. VIBRATION: Transportation – vibration → Physical instability. Ex: separation of powders, Gradual opening of

screw caps.

Biological hazards: MICROBIOLOGICAL HAZARDS: Contamination - Product spoilage, Health risk. Remedy : Closure -

reasonable seal & for repeated use. Sterile products - hermetically sealed. HUMANS: Tampering. Remedy: tamper proof

packaging.

SELECTION OF TYPE OF PACK: Factors required for selection: Product/ pack contents Application of product Content

stability Content reactivity with packing material (Drug compatibility) Accessibility of pack to user Packaging process

Regulatory, legal, quality issues

Containers:

Containers Immediate container – direct contact with article at all times Well closed container – protect contents from

extraneous solids or from loss of articles under ordinary conditions of handling, shipment, storage & distribution. Tight

container - protects from extraneous liquids, solids or vapors, from loss of articles & from efflorescence, deliquescence under

ordinary or customary conditions & capable of tight re-closure. Hermetic container - impervious to air or other gases under

ordinary or customary conditions of handling, shipment, storage & distribution. Sterile hermetic containers - injections and

parenteral administrations.

Single dose container - holds a quantity of drug intended as single dose & when opened, cannot be resealed with assurance of

sterility. Ex: fusion sealed ampoules, prefilled syringes. Multiple dose container - hermetic containers that permits withdrawal

of successive portions of contents without changing the strength or endangering the quality or purity Ex: vials.

PACKAGING MATERIALS:

PACKAGING MATERIALS Required characteristics: Protection from environmental conditions Non-reactive with product

Must not impart to the product taste/ odors Non-toxic FDA approved Tamper resistant Adaptable to commonly employed

high speed packaging equipment.

GLASS CONTAINERS:

GLASS CONTAINERS Advantages: Disadvantages: Superior protective quality Economical Easy availability Chemically

inert Impermeable Strong Rigid FDA approved Does not deteriorate with age Excellent barrier to many elements Availability

of colored glass (amber) . Fragile Heavy

Manufacture of glass: :

Manufacture of glass: 4 processes: Blowing – compressed air forms molten glass in cavity of metal mold. Drawing – molten

glass pulled through discs/ rollers that shape the soft glass. Pressing – mechanical force presses molten glass against side of

mold. Casting – gravity/ centrifugal force cause molten glass to form cavity of mold.

PLASTIC CONTAINERS:

PLASTIC CONTAINERS Polymers: Additives: Polyethylene Polypropylene PVC Polystyrene Polymethylmethacrylate

Polyethylene terephthalate Polytrifluoroethylene Amino formaldehydes Polyamides Antioxidant Antistatic agent Colors

Impact modifiers Lubricants Plasticizer Stabilizers

Materials :

Materials Polyethylene: Advantages: Good barrier against moisture. Unaffected by strong acids & strong bases. Low cost

Disadvantages: Lack of clarity High permeation rate of essential odors, flavors, oxygen.

PowerPoint Presentation:

Density – 0.91 – 0.96 determines physical characters like: Stiffness Moisture vapor transmission Stress cracking Clarity.

Antioxidants used: Ex: butylated hydroxyl toluene, Dilamyl thiodipropionate . Antistatic additives: Ex: polyethylene glycols,

Long chain fatty acids .

Polypropylene :

Polypropylene Advantages: Resistant to stress cracking. Chemically resistant to strong acids, strong bases, organic material.

(except hot aromatic/ halogenated solvents) Has high M.P. ∴ suitable for boilable packages, sterilisable packages.

Disadvantages:

Disadvantages Disadvantages Remedy Lack of clarity Brittleness at low temperature (Fragile at 0 0 F) construction of thinner

walls. blend with polyethylene/ other material

Polyvinylchloride: :

Polyvinylchloride: Advantages: Disadvantages: crystal clear good oxygen barrier greater stiffness inexpensive tough easily

processed should not be over heated poor impact resistance (280 0 F – degrade → degradation products are corrosive) Heat/

UV → yellow. (So, STABILIZER used) Dioctyl tin mercapto acetate/ malate

PowerPoint Presentation:

Uses: Fabrication of plastic bottles. Skin coating on glass bottles. It is done by dipping bottle in PVC plastisol and the coating

is cured that gives shatter resistant coating.

Polystyrene:

Polystyrene Advantages Disadvantages: Rigid Crystal clear Low cost Acid, base resistant (except strong oxidizing agent)

High water transmission High oxygen permeability Easily scratched Cracks easily Builds up static charge Low melting point

Attacked by chemicals – produces cracks.

DRUG – PLASTIC CONSIDERATIONS :

DRUG – PLASTIC CONSIDERATIONS Permeation Leaching Sorption Chemical reaction Alteration of physical properties

Permeation:

Permeation Transmission of gases/ vapors/ liquids through plastic packaging materials that affects shelf life. water vapor, O 2

→ hydrolysis, oxidation. Volatile ingredients → pass through container walls . Ex : aroma of cosmetic products →

objectionable. W/o emulsions – should not be stored in hydrophobic plastic bottle. ( Oil phase migrates & diffuse into plastic)

Leaching :

Leaching Migration of plastic container ingredients into product. Ex: coloring agents like dyes migrate into parenteral solution

making them toxic. Release of constituents from container → drug contamination.

Sorption :

Sorption Factors affecting sorption: Chemical structure pH solvent system concentration of API temperature length of contact

Area of contact. Removal of constituents from drug product by packaging material. Highly potent drugs – sorption → affects

therapeutic efficacy Ex: sorption of diazepam to low density plastics → loss of drug available for administration. ∴ Glass

containers preferred Loss of preservatives → microbial growth.

Chemical reactivity :

Chemical reactivity Ingredients in plastic containers react chemically with drug or vice-versa. Chemically incompatible

substances alter the appearance of either plastic or drug product.

Modification: Modification Physical & chemical alteration of packaging material by drug product → degradation Ex:

Deformation in polyethylene containers by permeation of gases/ vapors from environment through container walls. Oils-

softening effect on polyethylene. Fluorinated hydrocarbons – attack polyethylene, PVC. Surfactants - change in polyethylene.

Petroleum solvents – extract plasticizer in PVC → plastic hard & stiff.

thermal degradation of polyethylene carry bags made from standard polyethylene (bottom) and biodegradable

polyethylene (top). Pictures show (left to right) at 0, 30 and 55 days exposure. :

thermal degradation of polyethylene carry bags made from standard polyethylene (bottom) and biodegradable polyethylene

(top). Pictures show (left to right) at 0, 30 and 55 days exposure.

METALS :

METALS TIN ALUMINUM USES Foods, pharmaceuticals, tin coated plates thick – aerosol cans, tubes for effervescent

tablets Intermediate thickness – collapsible tubes, roll on cap Thinnest – flexible foils ADVANTAGES Chemically inert,

good appearance Light weight, strong, impermeable DISADVANTAGES expensive Corrosion.

RUBBERS :

RUBBERS USES stoppers cap liners bulbs for dropper assemblies seals closures gaskets in aerosol cans

Types – disadvantages :

Types – disadvantages Synthetic rubbers: butyl, bromobutyl, chlorobutyl, neoprene, nitrile, silicone

FIBROUS MATERIALS :

FIBROUS MATERIALS Paper – labels, sterile sachets Cardboard - cartons, dividers. Tyvek ® - paper packaging rolls

FOILS:

FOILS Thin sheets of metal with < 100µm thickness. Aluminum : Barrier Attractive, reflective surface . Thick aluminum

sheet - tray for blister pack Thin aluminum foil - vacuum dispositioning

FILMS :

FILMS Non- fibrous, non- metallic, < 250µ thickness. Cellophane: Attractive, transparent film Can be colored & printed

Used as outer wrap. Plastics: Moisture barrier – PVC, polypropylene Gas barrier – polyester, PVC, nylon Heat sealers –

nylon, polypropylene.

LAMINATES :

LAMINATES Made by bonding the layers with adhesive. Different layers from outside in: Decoration , information

Mechanical protection Light, moisture barrier Heat sealer . Disadvantage : Migration of adhesive into product. - PVC (may be

PP) - OPA Film - Aluminium foil - Primer/Adhesive - Primer/Adhesive

CLOSURES :

CLOSURES Functions: Provides stability to product Compatibility Prevents contents from escaping out Prevents entry of

foreign substances Basic designs: Screw on, threaded, or lug Crimp on (crowns) Press on (snap) Roll on Friction.

Threaded screw cap: :

Threaded screw cap: When screw cap is applied, its threads engage with the corresponding threads molded on neck of bottle.

Made of : Metal – tin/ aluminum Plastic – thermosetting/ thermoplastic. Metal caps - coated inside with enamel or lacquer for

resistance against corrosion. Thermosetting plastics have a cap insert composed of backing material coated with aluminum

lining or plastic film.

Lug cap: It is an interrupted thread on glass finish. A lug is engaged on cap side walls and cap is drawn to the sealing surface

of container. It forms a hermetic seal. Useful in sterilization equipment and on production lines.

Press on (snap) closure: Some closures snap on. To open, the top is designed to pry off/ break off/ or have a built in

dispenser.

Crown cap: These are shallow metal caps crimped into locking position around the head of bottle. Used as crimped closure

for beverage bottles.

Roll on closures :

Roll on closures A plain aluminum cap is pushed over the neck of container and force is applied from the side to make the

aluminum fit the shape of neck. If neck has a screw thread, then the cap is pressed to match the thread exactly. Advantages:

Easily opened Effectively resealed Economical Tamper evident

Applications: Packaging of food, beverages, chemicals, pharmaceuticals Safety device for bungs in vials Types: Resealable

Non resealable Pilfer proof

Friction fit closures :

Friction fit closures An interference fit or friction fit requires some force to closure and open, providing additional security.

CLOSURE LINERS: CLOSURE LINERS Liner: Material inserted in a cap to affect a seal between closure and container.

Backing material Facing material Types: Homogeneous liner Heterogeneous/ composite liner

Factors in selecting a liner:

Factors in selecting a liner Compatibility ( chemical resistance) Appearance Gas, vapor transmission rates Removal torque

Heat resistance Shelf life Economics.

TORQUE TESTING :

TORQUE TESTING Torque tester – to control cap tightness on a packaging line, Prevent evaporation of product. Prevent

leakage of product. Prevent breakage of plastic molded closure. Ex: Owens- Illinois torque tester .

RUBBER STOPPERS :

RUBBER STOPPERS Ingredients: Rubber Vulcanizing agent Accelerator/ activator Extended filler Reinforced filler

Softener/ plasticizer Antioxidant Pigment Special components, waxes

Rubber stoppers:

Rubber stoppers syringes vials

PLASTIC CLOSURES :

PLASTIC CLOSURES

TAMPER RESISTANT PACKAGING :

TAMPER RESISTANT PACKAGING 1982 – OTC drugs – malicious adulteration (tainting of Tylenol capsules with cyanide

→ deaths) Nov 5, 1982 – FDA – regulations - Federal Register. The Proprietary Association - recommendations to FDA .

FDA regulations 21 CFR parts 211, 314, 700.

According to FDA, “a tamper resistant package is one having an indicator or barrier to entry which, if breached or missing,

can reasonably be expected to provide visible evidence to consumers that tampering has occurred. Tamper resistant package

may involve immediate container or closure systems or secondary container or carton systems or any combination thereof

intended to provide a visual indication of package integrity when handled in a reasonable manner during manufacture,

distribution and retail display”.

Exceptions for tamper resistant pack: :

Exceptions for tamper resistant pack: Dentifrices Skin care products Insulin Throat lozenges

Examples :

Examples Film wrapper Blister package Strip package Bubble pack Shrink seals, bands Foil, paper or plastic pouches Bottle

seals Tape seals Breakable seals Sealable tubes Aerosol containers Sealed cartons

Film wrapper:

Film wrapper For products requiring package integrity or environmental protection . It can be generally categorized into the

following types: 1. End folded wrapper 2. Fin seal wrapper 3. Shrink wrapper 64

End Folded Wrapper: :

End Folded Wrapper: Formation: Push product into sheet of overwrapping film → film forms around product → edges fold in

gift wrap fashion → folded surfaces sealed by pressing against a heated bar. It should be well sealed, printed or uniquely

decorated. Materials used: Cellophane Polypropylene Polyvinylidene chloride (PVDC) Nitrocellulose. 65

END FOLDED WRAPPER:

END FOLDED WRAPPER

Fin Seal Wrapper:

Fin Seal Wrapper Formation: Crimp film together→ seal the two inside surfaces of film together → compress material

between two heater bars. It is opened by tearing the wrapper only Materials used: polyethylene, Surlyn (Du Pont’s Ionomer

Resin ) Advantages : Better seal integrity Protective packaging 67

Shrink wrapper:

Shrink wrapper - prepared by packaging in a thermoplastic film that stretches during manufacturing and un-stretches due to

application of heat. Formation : Film unwinds → pocket formed in center fold of sheet → product inserted → L-shaped sealer

seals overwrap & trims off excess → pass through heated tunnel → shrinks to tightly wrapped unit Materials used: heat

shrinkable materials – polypropylene, polyethylene, PVC. Advantages: Flexibility Low cost of packaging equipment. 69

Blister package :

Blister package Heat soften a sheet of thermoplastic resin → vacuum draw the softened sheet into mold → cool → remove

sheet from mold → send sheet to filling station for product → lid with heat sealable backing material. Backing material - 2

types : Push through – heat seal coated aluminum foil Peelable - polyester/ paper - Child resistant 71

Materials used in blister pack: Thermoformable blister – PVC - PVC / polyethylene combinations Moisture protection –

polyvinylidene chloride (Saran) or laminated to PVC Polychlorotrifluoroethylene ( Aclar ) Advantages of blister pack:

Excellent environmental protection, Esthetically pleasing and efficacious appearance. Convenience Child resistance Tamper-

resistance 73

STRIP PACKAGE :

STRIP PACKAGE Formation: Feed two webs of heat sealable flexible film through heated crimping roller/ reciprocating

plate → drop product into pocket → continuous strip of packets formed → cut to desired number of packets in length.

Materials used: For high barrier applications – paper/ polyethylene/ foil/ polyethylene lamination For product visibility – heat

sealable cellophane/ polyester Advantages: High degree of seal integrity (∵ sealing done between pressure rollers) Useful for

moisture sensitive products ( ∵ high barrier materials like foil laminations/ saran coated films used) Use: used for tablets and

capsules. 74

BUBBLE PACK :

BUBBLE PACK It is formed by sandwiching product between thermoforamble , extensible or heat shrinkable plastic film and

rigid . Formation: Heat soften plastic film → vacuum draw pocket into film → drop product into pocket → seal with heal

coated paperboard. If heat shrinkable material is used- pass package through a heated tunnel → film shrinks into a bubble

over product → firmly attaches to backing card

SHRINK BANDING :

SHRINK BANDING Formation: Heat shrinkable polymer is manufactured as an extruded, oriented tube in a diameter slightly

larger than cap & neck ring of bottle to be sealed It is supplied to bottler as a printed, collapsed tube, either precut to a

specified length or in roll for an automated operation. Proper length of PVC is slid over capped bottle Bottle passed through

heat tunnel → tubing shrinks tightly. For ease of opening, tear perforations are supplied.

FOIL, PAPER OR PLASTIC POUCHES :

FOIL, PAPER OR PLASTIC POUCHES Flexible pouch: Formation: Formed during product filling operation by equipment:

Vertical/ horizontal forming Filling Sealing Advantages : tamper resistant environmental protection 79

BOTTLE SEALS :

BOTTLE SEALS Inner seal is bound to rim of bottle that access to product is attained by irreparably destroying the seal.

Liners used: glassine, foil laminations. Glassine liners: Two sheets of glassine paper are bonded together with wax or

adhesive. Glue mounted inner seals Pressure sensitive inner seals Heat sensitive adhesive 84

TAPE SEALS :

TAPE SEALS Glued or pressure sensitive tape or label is applied around or over closure of package, which must be destroyed

to gain access to packaged product. High density light weight paper with poor tear strength. Labels of self - destructing paper.

Perforations or partial splitting of paper.

BREAKABLE CAPS :

BREAKABLE CAPS Roll-on cap – carbonated beverages. Aluminum shell is placed over bottle neck. Cap blank is held on

bottle under pressure, rollers crimp and contour the bottle thread into cap blank. Bottom portion is perforated that it breaks

away when cap is unscrewed. Ratchet style plastic cap - Bottom portion has a tear-away strip that engages a ratchet on bottle

neck.

SEALABLE TUBES :

SEALABLE TUBES Collapsible tubes Metal tubes Puncture inserts - Seal the tube opening - Punctured and pried out to

access product. Extruded plastic tubes Laminated tubes – high barrier protection

Sealable tubes:

Sealable tubes Aluminum tubes Plastic extruded tubes

Quality Control

1.DESCRIPTION

2. SUITABILITY

container closure system for its intended use.

intended use. It should protect and compatible and composed of material that

are considered as safe for use with dosage form.

reference standards, and validation information

3. PROTECTION

against cause of degradation like: light, temp, loss of solvent, exposure to reactive

gases, microbial contamination. Not every drug product is susceptible to degradation

by all of these factors.

se factors actually have an

influence on a particular drug product.

protection against microbes is essential then maintain adequate integrity after

packaging and during packaging.

4. COMPATIBILITY

should be determined.

and leaching can lead to degradation, precipitation, change in drug pH, discoloration

investigated and appropriate action should be taken.

5. SAFETY

atient will be exposed

when being treated with drug products.

appropriate like Extraction study on the packaging components to determine which

chemical species may migrate in to dosage form and then toxicological evaluation of

those substances,

COMPONENTS & EVALUATION

HITESH BULCHANDANI SSPC, MEHSANA

on good scientific principles and take into account the specific container closure

system, drug product formulation, dosage form, route of administration, and dose

regimen (chronic or short-term dosing).

6. PERFORMANCE

performance include:

i. Container closure system functionality

cap that contains a counter), minimize waste (e.g., a two-chamber vial or IV bag),

improve ease of use (e.g., a prefilled syringe), or have other functions.

ii. Drug delivery

in the amount or at the rate described in the package insert.

are a prefilled syringe, a transdermal patch, a metered tube, a dropper or spray bottle,

a dry powder inhaler, and a metered dose inhaler.

be used to ensure consistency in the packaging components.

and design tolerances should be defined and monitored.

monitor melting point and glass transitions of plastics, and IR scanning to prove identity should be a part of an

ongoing quality-control monitoring program.

WHOLE HUMAN BLOOD

• Definition : It is the human blood mixed with asuitable anticoagulant

That is :

Human Blood + Anticoagulant = Whole Human Blood

Conditions for Being a Donor

Any person in good health is accepted as a donor provided that he or

she:

1) Is not suffering from any disease that can be transmitted by

transfusion. This includes syphilis, malaria, and serum jaundice.

2) Is not anemic. The haemoglobin content of the blood should not

be less than

� 12.5% for females

� 13.3% for males

(checked by allowing a drop of blood to fall into a copper sulphate

solution of specific gravity 1.053 for females, and 1.055 for males. If

the drop sinks, the sample is satisfactory)

3) Has been taking medication which might prove toxic or have

allergic reactions in a patient e.g. antibiotics.

Collection of the blood

• Blood is collected aseptically from the median cubital vein, in the front elbow.

• This blood is put into a sterile container containing an anticoagulant solution and the

bottle is gently shaken to ensure that blood and anticoagulant are well mixed, thus

preventing the formation of small fibrin clots.

• A maximum of 420ml of blood is taken in one attendance.

• Immediately afterwards the container is sealed and cooled to 4‐6 degrees centigrade

for storage.

Equipment Used for the Collection

Equipment used for taking the blood is madefrom plastics, and is disposable

The container earlier consisted of bottles, butPlastic bags have started being used and arethe containers of the future.

Blood Clotting

Two important steps in the clotting of blood are:

PROTHROMBIN (Soluble) In presence of THROMBOPLASTIN +

IIn response to injury, the tissues and blood platelets free substances that activate the clot

promoting enzyme THROMBOPLASTIN.Thromboplastin, with the assistance of ionized calcium and other factors, converts

PROTHROMBIN to active clotting enzyme THROMBIN.Thrombin then acts on FIBRINOGEN, converting it into insoluble

FIBRIN, the matrix of the clot.

ANTICOAGULANTS

CITRATES

CITRATES

• The solution most often used as a blood

anticoagulant is known as Acid‐citratedextrose

(ACD), composed of:

– Sodium Citrate (2.0 to 2.5 g)

– Dextrose (3.0 g)

– Water for Injection (q.s. to 120 ml)

• The citrate prevents clotting by binding the calcium ions as unionized calcium citrate, thus preventing a vital step of clotting.

Why Acid Citrate and not Normal Citrate??

• Earlier the normal, trisodium citrate was used but

it has a very high alkaline pH in solution which

causes considerable caramelisation of the

dextrose (darkening) during sterilization and the

two solutions have to be autoclaved separately.

• The Acid Citrate produces a pH of about 5 and

causes little or no caramelisation.

• In addition, it is less likely to induce flaking of the

glass of the container.

• The higher concentration (2.5g / 120ml) is often preferred because it more effectively reduces the formation of small clots.

Why add Dextrose?

• The dextrose delays haemolysis of the

erythrocytes in vitro and prolongs their life

after transfusion.

• Its function is hypothesized to be connected

with the synthesis of compounds, such as ATP,

that are important in making energy available

to living cells.

HEPARIN

• Naturally occurring anticoagulant.

• Made by the mast cells of the connective

tissue surrounding blood vessels.

• It inhibits clotting in the circulatory system.

• Occasionally, it is used in blood for transfusion

when large volumes must be given to one

patient and the corresponding amounts of

citrate would be harmful, e.g. in cardiac

surgery.

It quickly loses activity in blood in vitro and

normal quantities are effective for about a day.

• ACD on the other hand, prolongs the storage

life to three weeks.

• Heparin is expensive and may continue its

action even after transfusion, thus needing

administration of neutralizing substances such

as protamine sulphate.

DISODIUM EDETATE

• This is also a chelating agent like ACD.

• It has a strong affinity for divalent metals, and

thus will bind to calcium firmly.

• It is sometimes preferred when preservation of

blood platelets is essential, although the stability

of these seems to depend much more on

preventing contact with the glass surface: if

plastic bags or silicone‐treated glass is used, ACD

is almost as effective as Disodium Edetate.

• The survival of red blood cells in dextrose‐edetate

solutions is as good as in ACD.

TESTING OF WHOLE BLOOD

• At the time that blood is collected, two small additional

amounts are collected:

– One, which is often obtained by draining the collecting tube, is

put into a small 5 ml bottle and is firmly attached to the main

container. This is for testing compatibility with the blood of the

recipient. This separate specimen avoids the dangerous

procedure of attempting to remove a sample from the main

bottle without causing bacterial contamination.

If a plastic bag is used, it is possible to leave the blood‐filled

collecting tube attached to the bag and to seal it at several

points with a special tool; then a section can be separated for

testing without contamination

– The second, somewhat larger sample is used as soon as possible

for :

• Serological test to confirm the absence of syphilis and other diseases

• To determine the ABO blood group of the cells and plasma and the Rh

grouping of the cells.

BLOOD GROUPS

• Fundamental Aim: is to prevent antigen‐antibody

reaction.

• Red cells carry an antigen that reacts with the

corresponding antibody in the plasma of

individuals of certain other groups. If the cells are

transfused into an individual with the equivalent

antibody in his plasma, they are rapidly

destroyed, with serious consequences.

• Although some 9 blood groups are known, only

the ABO and Rh are of major importance as

causes of haemolytic transfusion reactions

1) ABO System

• The first sign of the haemolytic antigen‐antibody

reaction is agglutination and, therefore, red‐cell

antigens and plasma antibodies are called

agglutinogens or agglutinins respectively.

• The agglutinated cells haemolyse, freeing

haemoglobin and other constituents and causing

jaundice and kidney damage: if the latter is

extreme, the patient may even die.

• Fortunately most transfusion reactions are mild.

Rh System

• Rh factor, so named cause it was found in the

rhesus monkey.

• The red cells of some individuals carry an

antigen that is known as the Rh factor.

• If Rh+ blood is transfused into an Rhrecipient,

production of antibodies to the Rh+

blood may be stimulated.

• If this occurs, subsequent transfusion of Rh+

blood will cause a haemolytic reaction.

• Haemolytic disease in a new born:

– If a foetus is Rh+ from it’s father, and the mother is

Rh‐ and has the Rh+ antibody in her blood (either

from previous transfusion of Rh+ blood or as a

result of stimulation by antigens of the foetus), the

mother’s antibodies may cross the placenta and

destroy the foetal erythrocytes.

– This haemolytic reaction may kill the foetus or

cause the infant to be severely anaemic.

STORAGE

• Blood collected must be kept at a temperature between 4

to 6 degrees centigrade, at all times except during short

periods of transport and examination, which must not

exceed 30 mins.

• Even at this low temperatures, deleterious changes do take

place.

– The leucocytes disintegrate in a few hours

– The platelets disintegrate in a few days

– The red cells show a fall in ATP and other organic phosphates, a

reduction in oxygen‐carrying capacity and, due partly to loss of

lipid from their membranes, increased fragility.

• Storage at room temperature even for a day, seriously

reduces post‐transfusion survival of the erythrocytes.

• The fitness of blood for transfusion is based on its appearance. On

standing, the cells sediment, leaving a layer of yellow supernatant

plasma.

• If the blood has been taken shortly after a heavy fatty meal, the plasma

may be turbid and show a white layer of fat on it’s surface. On top of

the red cells there may be a complete or partial greyish layer of

leucocytes.

• The most important feature, however, is the line of demarcation

between cells and plasma, which must be sharp: if it is obscured by a

diffuse red coloration, indicating haemolysis, the blood is unfit for use.

• Complete haemolysis, especially if it occurs rapidly, is usually a sign of

bacterial infection, but its absence is not confirmation of sterility since

certain psychrophilic bacteria, predominately pseudomonads and

members of the coli‐aerogenes group, can grow in blood at refrigerator

temperatures without causing haemolysis.

• Many of the organisms isolated from contaminated blood have been

capable of using citrate as their sole source of carbon and, as would be

expected, this has led to clot formation, as citrate which is the

anticoagulant gets assimilated by the bacteria.

USES

• Haemorrhage, shock, burns and uncontrollable diarrhoea and

vomiting, can all cause significant losses of blood.

– Haemorrhage and other diseases may result in deficiency or

absence of vital blood constituents such as red cells, platelets, or

clotting factors.

– The transfusion of whole blood can be of great value in all these

circumstances but often, because of the risk of transfusion

reactions, it is not used where the need is solely to make up blood

volume but is restricted to haemorrhage and certain diseases

where there is deficiency of the vital oxygen‐carrying erythrocytes.

• Normally whole blood is not administered unless the ABO and

Rh groups of the donor and recipient are known and a sample

of the donor’s blood has been tested for compatibility with

that of the recipient.

• In an emergency, group O, Rh negative blood may be given

while taking necessary precautions.

CONCENTRATED HUMAN RED BLOOD

CORPUSCLES

Definition: This is the solution of human RBC’s

which have been concentrated using

centrifugation

Preparation

• It is prepared by removing most of the citrated plasma from wholeblood that is not more than a fortnight old and has been

allowed tostand or has been centrifuged to deposit the cells

•More than 40% of the supernatant fluid after the settling, is siphonedoff using sterile tubes, taking strict aseptic precautions

throughout.

• Since there is a risk of bacterial contamination the product must beused within 12 hours.

• The cells are matched with the recipient’s plasma and may then bemixed with matched cells from other bottles.

• The haemoglobin content must not be less than 15.5%

Uses

• This product is used when administration ofwhole blood might overtax the circulation, i.e., intreatment of diseases, such as

chronic anaemia(where blood volume has not been reduced),rather than haemorrhage (which would require areplenishment of

blood volume as well and thuswould require whole blood)

• Another application is in exchange transfusion in

infants: a toxic amount of citrate might be given if

whole blood was used.

DRIED HUMAN PLASMA

• It is the portion of the blood which has been separated from the cell content, and is dried, and can be used after

reconstitution with water.

Problems to be Overcome During Preparation

• Two major problems have to be overcome

– Transmission of Viral Jaundice

– Neutralization of Plasma Agglutinins.

1] Transmission of Viral Jaundice

• There are two types:

– Infective hepatitis (incubation time = 5 weeks, mortality rate = 0.3%)

– Homologous serum jaundice (incubation time = 20

weeks, mortality rate = 12%)

• Most infections following transfusion are mild

• Control is partly effected by refusing to accept donors with a history of jaundice, but not all cases are recognized and since

at present there is no

reliable test by which carriers can be detected, an occasional infected bottle is inevitable.

• Attempts have been made to kill the causative

viruses by treatment with UV light, but the method

is technically difficult.

• Note – if the preparation of a blood product involves pooling material from a larger number of donors, infection in one or

two bottles will be

distributed throughout the pool and appear in each of the units made from it.

• Nowadays, the pools used for making dried plasma and serum are limited to not more than ten donations, and the incidence

of jaundice is only

slightly greater than when whole blood is transfused.

• However, in the past, when pools of 300 or more bottles were made, the incidence was 7 to 12%.

Preparation of Dried Plasma

• Dried plasma is usually prepared from time‐expired citrated blood

• The blood is centrifuged as in the case of concentrated red blood cells and the supernatant fluid is siphoned off.

• This siphoned fluid is then combined and batches of less than 10 bottles are pooled, choosing the correct ratio of blood

groups to neutralize the powerful agglutinins

• The pools are kept at 4 to 6 degrees centigrade while samples are tested for

sterility and no pool is used unless it passes

• Then 400ml quantities are dispensed into bottles and subjected to freeze drying.

• General aspects of freeze drying are followed with special features of the plasma

process‐ • Preliminary Freezing

• Primary Drying

• Secondary drying.

Preliminary Freezing

• The bottles are sealed with bacteriologically efficient fabric pads covered by ring‐type closures and then centrifuged at

‐18degrees

centigrade.

• The liquid snap‐freezes and becomes distributed around the inside of the bottle.

Primary Drying

• The bottles of frozen material are mounted horizontally in the drying chamber and a high vacuum is applied.

• The ice sublimes on to a condensing coil kept at ‐50 degrees centigrade and a small heater provides the latent heat required

for evaporation.

• This stage takes about 2 days, after which the residual moisture content is about 2%. Secondary Drying

• This is done in another chamber by vacuum desiccation over phosphorous pentoxide.

• It takes about a day, and the product is left with about 0.5% of moisture

• Each fabric seal is then replaced by an MRC type closure perforated by a plugged hypodermic needle. The bottles are

returned to the secondary drying chamber, re‐evacuated, and then the vacuum is broken with dry sterile nitrogen.

• Finally, the needles are removed and the closure is protected with a sterile viscose cap.

Storage

• Dried plasma, kept below 20 degrees centigrade and protected from light, moisture, and oxygen, remains usable almost

indefinitely, although it is customary to impose an arbitrary expiry date of about 5 years.

• Its fitness for use is shown by its solubility when reconstituted in a volume of water for injection (WFI), Sodium Chloride

Injection or a solution containing 2.5% dextrose and 0.45% sodium chloride, equivalent to the original volume of plasma.

• It must dissolve completely within ten minutes at room temperature.

• Gel formation or incomplete solution indicates deterioration.

• After reconstitution it must be used immediately.

Uses

• Reconstituted plasma is satisfactory alternative to whole blood in conditions where there is no loss of red cells.

• It is of particular value in the treatment of severe burns and scalds where, because of extensive fluid and protein

loss, there is considerable haemo‐concentration.

• It may also be given when blood is more appropriate; either because whole blood is unavailable or, in emergency, until the

results of matching tests are known.

• Because of its long storage life at a convenient temperature, dried plasma is more suitable than blood as a reserve stock in a

small hospital or a remote community.

DRIED HUMAN SERUM

• Prepared in the same way as dried plasma except that

the blood is collected into dry bottles and allowed to clot.

• The supernatant serum being separated after the clot has

retracted.

•Plasma is usually obtained from blood that is out‐of‐date, i.e. has been available

as whole blood for 21 days.

•By converting blood into serum this period in reserve is lost and, therefore, much

less blood is used for serum production

Its, storage and use are the same as for dried plasma.

LIQUID PLASMA AND SERUM

• The only official liquid blood product is humanplasma protein fraction.Why unmodified liquid plasma and serum are no

longer recognized??

• Plasma and serum, like blood, are excellent media for bacterialgrowth and, therefore, the user must be able to detect

contamination.

• Unfortunately, these products are often opalescent due tosuspended fat.

• Further, turbidity and deposits develop during storage and as aresult of movement during transport, thus making infection

verydifficult to identify.

• Attempts to remove fat by filtration were not very successfulbecause it blocked the filter, but centrifugation proved more

satisfactory.

• With serum it was then possible, by passing the product through asterilizing pad, to obtain a clear preparation that would

storereasonably well. It has passed out of use because blood is moreeconomically used for dried plasma production.

Further progress was made less urgent by the success of driedplasma but investigations continued and have contributed to the

development of the product known as human plasma proteinfraction.

THE FRACTIONATION OF PLASMA

• About 60% of plasma protein is albumin and,therefore, it plays a major part in maintaining thehigh osmotic pressure

necessary to retain fluid in the blood vessels.

• A very successful solvent precipitation techniquewas developed by which other proteins, as wellas albumin, were separated.

• Some of these, i.e. fibrinogen, prothrombin, andgamma globulin, proved so valuable that proteinfractionation of plasma

quickly became anestablished procedure.Techniques of Protein Separation

• One of the oldest methods of protein separation issalting‐out, but this is unsuitable for plasmafractionation because high

concentrations of salt are needed and these are not selective enough. Also,dialysis, a technique that is difficult to perform

aseptically, is necessary to remove the salt after theprecipitation.

• E. J. Cohn and his colleagues (due to the need for

transfusion material with a long life and stability, unlike whole blood, during the early part of the Second World

War), had developed a technique to separate albumin and other proteins from plasma.

• Cohn’s technique was based on the use of an organic solvent (ethyl alcohol) to reduce the solubilities of the

proteins, and was given flexibility by alterations of pH, ionic strength (i.e., salt concentrations) and protein.

• The use of an organic solvent, instead of salt, as a major precipitant confers a number of incidental advantages:

– Because of its volatility it can be removed easily during the freeze drying of the final product.

– Salt can be used in low concentrations to improve resolution.

– It helps to control contaminants because of its bacteriostatic activity.

– Being a liquid, it is easy to add aseptically

• On the other hand, it is necessary to keep the

temperature very low (0 to ‐5 degrees centigrade) to

prevent solvent denaturation of proteins.

Human Fibrinogen

• Fibrinogen is the soluble constituent of plasma which on addition of

thrombin is converted to fibrin (which is insoluble).

• After separation from plasma by fractionation, the precipitate is

collected by centrifugation, dissolved in citrate‐saline, and freeze

dried

• The air in the containers displaced by nitrogen.

• The citrate prevents spontaneous clotting when the material is

reconstituted.

• Fibrinogen dissolves slowly. However, like many other protein

solutions, it froths a lot if shaken and the solid‐stabilized foam is very

slow to disperse, thus agitation should be limited to rocking.

• The solution should be used as soon as possible and not later than

three hours after preparation.

• The fibrinogen must be stored under dry conditions, protected from

light and at a temperature below 20 degrees centigrade. The other

storage conditions are similar to that of dried serum.

Use of Human Fibrinogen

• Occasionally, fibrinogen is administered alone

to treat fibrinogen deficiency.

• But it is more often used in conjunction with

thrombin as will be seen ahead.

Human Thrombin

• Thrombin is an enzyme that converts fibrinogen to fibrin.

• The prothrombin obtained from the fractionation of plasma

is washed with distilled water and dissolved in citrate

saline.

• It is converted to thrombin by adjustment of pH to 7 and

adding thromboplastin and calcium ions.

• The solution is filtered and freeze dried, and the air in the

containers is replaced by nitrogen.

• It is reconstituted with saline when required.

• The thrombin must be stored under dry conditions,

protected from light and at a temperature below 20

degrees centigrade. The other storage conditions are

similar to that of dried serum.

Uses of Human Thrombin

• The fibrin clot produced when thrombin is mixed with

fibrinogen is used in surgery to suture severed nerves

and to assist adhesion of skin grafts.

• The mixture clots at a rate that depends on the amount

of thrombin present and, therefore, if necessary, it can

be kept fluid long enough for adjustments, e.g. of skin

grafts to be made.

• The clot also acts as a haemostat (which will be seen

ahead in Human Fibrin Foam).

• Since the fibrin is human, it is well‐tolerated by the

body, and new cells penetrate it rapidly allowing a

quicker and better healing to occur.

Human Normal Immunoglobulin

Injection

• Immuno‐ or gamma globulin is obtained from the

globulins fraction separated in stage 3 of the fractionation

of plasma, as had been shown earlier.

• The ionic strengths are critical and further fractionation is

done as follows:

The immunoglobulins are dissolved in a suitable

solvent, usually 0.8% sodium chloride solution,

and a preservative, e.g. 0.01% thiomersal, is

added.

• The solution is sterilized by filtration, packed in

single‐dose containers and stored at 4 to 6

degrees centigrade, with protection from light.

• Normally pools of not less than 1500 donations

are used to ensure a satisfactory representation of

the various types of adult antibodies.

• However, as in the preparation of antivaccinia and

antitetanus immunoglobulins, which is obtained

from the blood of recently immunized donors, the

pools of blood can be smaller.

Uses of Immunoglobulins

• Used to prevent or attenuate diseases such as

– Measles

– Rubella

– infectious hepatitis

– hepatitis B

– Chickenpox

– Hypogammaglobulinaemia (deficiency in gamma globulins)

• It is used to prepare specific immunoglobulins such as:

– Human Anti‐Vaccinia Immunoglobulin – for small pox

– Human Anti‐Tetanus Immunoglobulin

– Human Anti‐D Immunoglobulin – used to suppress sensitization of

Rh –ve mothers to the Rh(D) antigen (Rh +ve infant)

– Anti‐HBsImmunoglobulin – this is still under investigation. It is an

immunoglobulin for Hepatitis B surface antigen.

QUALITY CONTROL OF BLOOD PRODUCTS

Sterility and Pyrogens

• All blood products must comply with the

official tests for sterility, and those

preparations (i.e. immunoglobulins and the

plasma protein fractions) that are exposed to

special risk of contamination with pyrogens

due to lengthy processing must also pass the

test for pyrogens.

Solubility

• Complete solubility in an appropriate volume

of the usual solvent, sometimes in a specified

time, is required for all solid preparations

except fibrin foam.

• It indicates that the protein constituents have

not deteriorated.

Assays

• For whole blood and concentrated RBCs the assay is a

determination of the haemoglobin value.

• For the remaining products, except fibrin foam (which has

no assay) and thrombin, the protein constituent is

determined chemically.

• In thrombin there must be a minimum number of clotting

doses per mg, a clotting dose being the amount of

thrombin required to clot 1ml of 0.1% fibrinogen in saline

buffered at 7.2 to 7.3 in 15 seconds at 37 degrees

centigrade.

• Determinations of Na and K ions in plasma protein fraction

ensures that the level are not high enough to disturb the

electrolyte balance of the recipient.

• An assay for sodium citrate in the same product prevents

toxic effects from excess of this salt.

Labelling for Whole Blood

Name of Preparation

• ABO Group

• Rh group and nature of antisera used for testing

• Total Volume; proportion of blood; nature and percentage of

anticoagulant and any other material introduced

• Date of Donation

• Expiry date

• Storage Conditions

• A statement that the contents must not be used if there is any sign

of deterioration

• An indication by which the history of the preparation can be traced.

Labelling of Dried Plasma Protein Fraction

Name of Preparation

• Volume of water of injection necessary for reconstitution

• Total amount of protein in reconstituted solution

• Concentrations of potassium, sodium and citrate ions

• Names and concentrations of stabilizing agents or other added substances

• Expiry Date

• Storage Conditions

• A statement that the contents must not be used if, after adding water, a gel forms or solution is incomplete

• An indication by which the history of the preparation can be traced

• An instruction to discard the reconstituted solution if not used within three Hours.

PLASMA SUBSTITUTES

The need for plasma substitutes?

• The limited supplies of plasma, the cost of

producing the dried form and the risk of

transmitting serum hepatitis stimulated

attempts to find substitutes of non‐human

origin that could be used to restore the blood

volume temporarily while the recipient

replaced the lost protein.

Properties of an Ideal Plasma Substitute

1. The same colloidal osmotic pressure as whole blood.

2. A viscosity similar to that of plasma.

3. A molecular weight such that the molecules do not easily diffuse

through the capillary walls.

4. A fairly low rate of excretion or destruction by the body.

5. Eventual and complete elimination from the body.

6. Freedom from toxicity, e.g. no impairment of renal function.

7. Freedom from antigenicity, pyrogenicity, and confusing effects on

important tests such as blood grouping and the erythrocyte

sedimentation rate.

8. Isotonicity, in solution, equal to that of blood plasma.

9. High stability in liquid form at normal and sterilizing temperatures

and during transport and storage.

10. Ease of preparation, ready availability and low cost.

Gum Saline

• This is a synonym for Injection of Sodium Chloride

and Acacia, which was official in the 1932 British

Pharmacopoeia.

• In the First World War Bayliss experimented with

soluble starch, dextrin, and gelatin as plasma

substitutes and finally used 6% acacia in 0.9%

Sodium Chloride solution.

• It was transfused extensively until signs of liver

dysfunction disclosed that the gum was not

metabolized but stored in various organs.

Polyvinylpyrrolidone

• In the Second World War, the Germans introduced a synthetic colloid,

polyvinylpyrolidone, for the treatment of shock.

• It was marketed in the 1950s but was later withdrawn because of suspected carcinogenicity.

Dextran

• To date this is the most satisfactory plasma substitute.

• It is a polysaccharide produced when the bacterium Leuconostoc mesenteroides is grown in a sucrose‐containing medium.

• In the sugar industry it occurs as a slime that clogs pipes and filters and interferes with crystallization.

The organism secretes an enzyme that converts sucrose to dextran according to the following equation‐

• Different strains produce dextrans of two main groups‐ – Long, practically unbranched chains of glucose units joined by 1‐6 glucosidic linkages.

– Highly branched polymers consisting of short chains

of 1‐6 units joined by 1‐4 and 1‐3 linkages to

branches. Branched chains are more likely to give rise toallergic reactions when injected, and indextrans used for plasma

substitutes thelinkages should be almost entirely of the 1‐6type. This is achieved by choosing a suitablespecially developed

strain of the organismthat produces dextran in which about 95% of the linkages are 1‐6.

Production

• Production involves laboratory culture followed by growth in

seed tanks in the factory and then in 4500 cubic dm

fermenters. (similar process to antibiotic production).

• Because synthesis of the enzyme and its action on the

sucrose are rapid, the high degree of asepsis maintained in

antibiotic fermentation is not necessary here.

• Also, as the process is inhibited by aeration, there is no need

for a costly supply of sterile air.

• Another special feature is the need to prevent the hydrolysis

of sucrose to glucose and fructose during sterilization of the

culture media. If this occurs, dextran will not be produced

because in nature the conversion does not involve inversion

but is a straight transglycosidation. Preventive measures

include adjustment of the media to neutral pH before

sterilization, and the avoidance of overheating.

When maximum conversion to dextran has been obtained

it is precipitated by adding a suitable organic solvent.

• Natural dextran consists of chains of approximately 200,000 glucose units with molecular weights up to about 50 million.

• Very large molecules i.e. those with a molecular weight above about 250,000 have serious drawbacks:

– They yield very viscous solutions that are difficult to administer.

– They may cause renal damage and allergic reactions.

– They interfere with blood matching and sedimentation tests

by causing rouleaux formation. Rouleaux are aggregates of red

cells that resemble piles of plates.

– They produce colloidal osmotic pressures that are lower than

those of small molecules.

summarize

Control for Dextran

• The following tests from the official specification

for Dextran 110 Injection illustrate the

precautions taken to confirm that the product is

suitable as a plasma substitute.

• Chemical techniques limit the amount of lead,

acetone and alcohol, reducing sugars, nitrogen (from culture medium) and acid and alkali.

• Biological methods show that the preparation is not pyrogenic, is sterile, and is free from proteins that could cause

anaphylaxis.

• The dextran content is determined by polarimetry and there are limit tests for small and large molecules.

– The former involves the injection into rabbits; the urine collected throughout the succeeding 48 hours must not contain more

than 30% of the injected dose. (as small molecules are excreted in the urine).

– The latter necessitates precipitation of the top 10% of the

fraction with alcohol and determining its intrinsic

viscosity; this must not be greater than 0.4% which is

equivalent to an average molecular weight of about

240,000.

– The intrinsic viscosity of the fraction as a whole is also

found and must indicate an average molecular weight of

about 110,000.

Dextran 40 Injection

• A number of conditions, including severe burns, crush

injuries and acute peritonitis, are accompanied by a severe

degree of sludging in the blood.

• This can be reduced by the administration of Dextran 40

injection which, because it contains polymers of low

molecular weight, lowers plasma viscosity and improves

capillary flow.

• Both changes reduce cell aggregation and this in turn,

further improves the flow.

• A crude dextran of low molecular weight is manufactured

by including very small template molecules in the

fermentation medium.

• Then fractionation is used to produce the clinical material

which has an average molecular weight of 40,000.

Absorbable Haemostats

• These materials are used to control bleeding

when it cannot be checked by more

conventional means.

• They are gradually absorbed by the tissue and,

therefore, if used during surgery can be left in

the body when the incision is closed, and if

applied to a surface wound need not be

removed when the dressing is changed.

• There are four important types:

– Human Fibrin Foam (which has been covered

earlier)

– Gelatin Sponge

– Oxidized cellulose

– Calcium Alginate

Absorbable Gelatin Sponge

• This is prepared by adding a small percentage of

formaldehyde to a warm solution of good quality gelatin.

• Which is then whisked into a foam and freeze‐dried.

• The porous product is cut into pieces of suitable size and

sterilized by dry heat at 140 degrees centigrade.

It is marketed as while or near white, rectangular, very

porous pieces that are extremely light and have a papery

feel.

• It absorbs many times its own weight of blood and the

official standard for absorbency requires absorption of

not less than thirty times it’s weight of water.

• When pressed tightly on to a bleeding area, blood is

taken up and clotting is encouraged by the large rough

surface which causes platelet disintegration.

• The sponge also acts as a plug by sticking to the

underlying tissues and mechanically supporting the clot

over the oozing vessels.

• Some times it is previously soaked in saline, antibiotic or

thrombin solution, when it must be pressed to remove

air and excess liquid before application.

It is marketed as while or near white, rectangular, very

porous pieces that are extremely light and have a papery feel.

• It absorbs many times its own weight of blood and the

official standard for absorbency requires absorption of

not less than thirty times it’s weight of water.

• When pressed tightly on to a bleeding area, blood is

taken up and clotting is encouraged by the large rough

surface which causes platelet disintegration.

• The sponge also acts as a plug by sticking to the

underlying tissues and mechanically supporting the clot

over the oozing vessels.

• Some times it is previously soaked in saline, antibiotic or thrombin solution, when it must be pressed to remove air and

excess liquid before application. Gaseous sterilization, often by formaldehyde, is used because heat causes serious

deterioration.

• The material has the appearance of the original dressing except that it may be less white in colour .

• It has a faint odour and acid taste.

• In contact with blood it turns dark brown and swells to a gelatinous coagulum. Small pieces are absorbed in 2 to 7 days but

very large

amounts may take several weeks.

• It inactivates thrombin, unless previously neutralized with sodium bicarbonate injection, and is incompatible with penicillin.

Calcium Alginate

• This is derived from alginic acid, a colloidal substance obtained from seaweeds Laminaria digitata and Laminaria cloustoni

which grow off

the scottish and Irish coasts.

• Alginic acid is a polyuronide built up from dmannuronic acid units.

• Its carboxyl groups react with the metallic ions to form alginates and, since the parent acid is unstable, the water‐soluble

sodium salt is used as

the source of other alginates. If ionized calcium salt is added to sodium

alginate solution instantaneous precipitation of calcium alginate occurs, a sensitive reaction that can be used for preparing

foams, fabrics

and other physical forms.

• These can be sterilized by autoclaving or dry heat.

• Alginate dressings can be removed, if necessary,by washing with a solution of sodium salt, e.g.

5% sodium citrate, which reverses the reaction shown in the equation above.

• They are compatible with penicillin and can be resterilized if necessary.

Calcium alginate dressings have a marked haemostatic effect that is probably due mainly to mechanical pressure.

HAIR STRUCTURE

Hairs are elongated keratinized structures. Keratin is a special protein, which is resistant to wear and tear. It is the protein that

also makes up the nails. Like other proteins in the body, keratin is also a large molecule made up of smaller units called amino

acids. The amino acids are joined together in a chain, like beads on a string.

The diameter of a single hair fiber varies from person to person; but it is usually around 0.05 to 0.09 millimeters. The

epidermis is the outermost layer of the skin. Each hair arises from an indentation on the epidermis. The hair has two parts: the

hair follicle and the hair shaft.

HAIR FOLLICLE

The hair follicle is the point from which the hair grows. It is a tiny cup-shaped pit buried in the fat of the scalp.

The terminal part of the hair follicle seated within the skin is called a hair bulb. The hair bulb is the structure formed by

actively growing cells. These cells produce the long, fine and cylindrically shaped hair fibers. Here in the hair bulb, there are

some special cells, which produce the pigment that gives the hair its color. This pigment is called melanin and the cells

producing it are known as melanocytes. We also know that receptors for the male hormones - androgens, are located on the

cells of this structure.

At the base of each hair bulb is the dermal papilla containing a vessel tuft. Thus, it is essential for the nourishment of the

growing hairs. Within the skin, internal and external root sheaths cover the hair follicles. The external root sheath of a hair

follicle is continuous along with the epidermis. There are also some glands adjacent to the hair follicles. The most important

one of these glands is the sebaceous gland, which produces and secretes the natural oils lubricating hairs, namely sebum.

HAIR SHAFT

The part of the hair seen above the skin is called the hair shaft. The hair shaft is made up of dead cells that have turned into

keratin and binding material, together with small amounts of water. This structure explains why we do not feel any pain while

our hair is being cut.

The hair shaft is formed by three layers. The innermost layer of the hair shaft is named the medulla. It is seen only in large

and thick hairs. The middle layer of the hair shaft is called the cortex, made of keratin fibers. The strength, color and texture

of a hair fiber are provided by the cortex layer of the hair shaft. The outermost layer of the hair shaft is the cuticle. This thin

and colorless layer made up of between six to ten overlapping layers of long cell remnants, serves as a protection to the

cortex.

Functions of hair:

How Our Hair Keeps Us WarmThe main function of the hair is the either warm us up or cool us

down. When we are hot, the hair lies flatter against the skin and therefore allowing less heat to break

through. When we are cold, the hair stands on end to trap more heat and warm up the body. The way

the hair moves is through the arrectorpili muscle located in the dermis layer of the skin. This tiny

muscle controls how the hair lays on the skin. When warm, the hair lies flat. When cold, the hair

stands up and the skin breaks into goose bumps, which is the skin raising up to collect more warmth.

3. How our hair protects usHair grows all over our bodies – the only places it doesn’t grow are on

our lips, the soles of our feet, our palms and our eye lids. Hair grows faster during the Summer and

slower at night than during the day. The ways in which our skin protects us areRegulating our body

temperatureControlling the loss of life sustaining fluids such as blood and waterProtects us from the

sun’s damaging ultra-violet rays.

NAIL POLISH

A clear or colored cosmetic lacquer applied to the fingernails or toenails.

Formulation::

Formulation: Nail lacquer system Lacquer base Colouring agents Other Formulating agent Film former Dyes Suspending

agents Resin Lakes Opacifying agents Solvent Pigments UV absorbers Plasticizer Pearl essence Perf ume 6

PowerPoint Presentation:

Film formers: Impart hardness, toughness, resistance to abrasion , viscosity to some extent. Nitrocellulose-widely used , based

on viscosity , SR nitrocellulose :10.7 to 11.2% N 2 RR nitrocellulose :11.2 to 12.8% N 2 Other examples include cellulose

acetate , cellulose acetate butylate , ethyl cellulose, vinyl polymers and various polymers of methacrylate . Resins: It impart

adhesion and improve gloss , help in dispersing insoluble pigments and lakes. Natural resins : Shellac, benzoin , gum dammar,

sandarac, ester gums. Synthetic resins: Sulphonamide -formaldehyde resins (poly aryl sulphonamides ). Commercial resins :

Santolite MHP : Claimed to Increase hardness of nitrocellulose and impart gloss to it. Santolite MS 80% : Claimed to increase

moisture resistance. 7

PowerPoint Presentation:

Solvents: Solvents are volatile organic liquids that combine all the ingredients of lacquer formulation and make a

homogeneous viscous preparation. Impart brushability and for regulating its drying time , viscosity of the preparation. High

BP-gives a brighter film . Low BP-Lowers viscosity and covering power. Solvents are in 3 inter-related categories: 1. Active

solvents : True solvents Eg., esters, ketones and glycol ethers for Nitrocellulose. 2. Couplers : Not solvents but in conjugation

increase the strength of other solvents. 3. Diluents : Diluents are non-solvents for nitrocellulose . These are used to stabilize

viscosity, to carry resins in solution and to reduce the effect of subsequent applications on the coat of enamel already applied,

to lower the overall cost of the product. Eg., Aromatic and aliphatic hydrocarbons and alcohols like Toulene, benzene, xylene,

hexane, heptanes, naphthas, light petroleum ether. 8

PowerPoint Presentation:

Plasticizer : They impart flexibility and adhesiveness to the film , and also effect viscosity and the volatility or rate of drying .

Two types of plasticizers: Solvent plasticizers : Act as solvents and are of high molecular weight. Eg., Butyl acetyl

ricenoleate. Non-Solvents plasticizers: Act as a softener. Eg., Castor oil. Colouring agents: Impart acceptable shade to the

lacquer base . The colouring agents must comply with the terms of Drug and Cosmetic act , should disperse well , be resistant

to light , acids and alkali found in detergents , be non-staining and produce a good gloss. Dyes: Soluble dyes alone normally

cannot impart sufficient depth of colour ,abandoned due to staining the surface & surroundings of the nail. Eg., Eosin,

erythrosine, carmosine, rhodamine Lakes : Insoluble lakes are incorporated to produce suitable shades. Eg., Colour lakes

mentioned in Schedule Q to Drug and Cosmetics Act rules. 9

PowerPoint Presentation:

Pigments : Insoluble in lacquers. Eg ., Titanium dioxide,iron oxide,Ultramarine blue, Chrome oxide green. Pearl essence:

Pearl essence is a suspension of crystalline guanine ( 2-amino-6-hydroxy purine ) in nitrocellulose and solvents. Bismuth

oxychloride , mica coated with titanium dioxide, pure aluminium and silver powder are also used . Other formulating agents:

Suspending agents : Suspending properties have been achieved by developing thixotropic system using pre-heated colloidal

clays. Eg ., Benzyl dimethyl hydrogenated tallow Ammonium montmorillonite ( Bentone 27) Dimethyl dioctadecyl

ammonium bentonite ( Bentone 34) Opacifying agents : These are whitening agents which help to develop shades which will

reflect the same colour on the nails as they are in the bottle. Eg ., Titanium dioxide, Zinc oxide. UV absorbers : To prevent

deterioration of ingredients due to UV light . Eg ., Benzophenones and its derivatives. Perfume : used mainly to counteract the

unpleasant odour of the solvents . Eg., Synthetic perfumes are preferred.

The steps:

1.) The pigments are mixed with nitrocellulose and plasticizer using a "two-roll" differential speed mill. This

mill grinds the pigment between a pair of rollers that are able to work with increasing speed as the pigment is

ground down. The goal is to produce fine dispersion of the color.

2.) When properly and fully milled, the mixture is removed from the mill in sheet form and then broken up into

small chips for mixing with the solvent. The mixing is performed in stainless steel kettles that can hold

anywhere from 5 to 2,000 gallons. The temperature of the kettle, and the rate of cooling, are controlled by both

computers and technicians. This step is performed in a special room or area designed to control the hazards of

fire and explosion.

3.) Materials are mixed in computerized, closed kettles. At the end of the process, the mix is cooled slightly

before the addition of such other materials as perfumes and moisturizers.

4.) The mixture is then pumped into smaller, 55 gallon drums, and then trucked to a production line. The

finished nail polish is pumped into explosion proof pumps, and then into smaller bottles suitable for the retail

market.

After the nails are actually provided a fundamental manicure, which involves cleansing the nail, getting rid of the cuticle and

virtually any dead skin around the edge of the nail.

The nails can easily then be actually delivered a base coat (typically a sturdy vivid white) to enhance a colored layout.

Or if the customer wants to have a natural look in the rear field of the layout, then no base coat is required. Then the activation

fur is applied - this provides that the design dries quickly.

The client chooses their design either from preset designs or from thier own image - which can be actually browsed into the

computer. After putting the hand into the machine the design are able to at that point be actually printed.

The printing itself takes roughly 10 seconds per nail, and pends on the layout - sometimes also quicker. The entire procedure

featuring nail preperation and drying of furs in between are able to take 15 minutes. They last as long as a typical Figuring out

Far more About Nail Polish or varnish therapy. By having the application of two sheer furs of clear nail varnish - paying

unique attention to the points, at that point if you are actually carefull by having you are nails, the layouts may last up 2 weeks

or longer.

LIPSTICK

Colored cosmetic applied to the lips from a small solid stick.

Composition :

Composition Wax mixture Oil mixture Bromo mixture Colors Preservatives Fragrance Antioxidants Surfactants & other

additives

WAXES :

WAXES The gloss & hardness are generally depends on characteristics & quantity of waxes Best characteristic is obtained by

using mixture of waxes of different m.p & adjusting the final m.p. by incorporating a sufficient amount of high m.p. wax.

OILS :

OILS The oil mixture is required to blend properly with the waxes to provide a suitable film on the applied lip skin. Also acts

as solvent in some formulation. Acts as dispersing agent for insoluble pigments. The ideal mixture of oil should produce the

product, easily spread & produce a thin film with good covering power. Examples: Castor oil Tetrahydrofurfuryl alcohol

(THFA) & esters Fatty acid alkylamides Paraffin oil Isopropyl myristate Isopropyl palmitate Butyl stearate

BROMO MIXTURE :

BROMO MIXTURE Maintain the physical form of the formulation Also called as bromo acids Two classes: Red : gives red

or reddish blue stain Orange , red : gives pink to yellowish pink stain About 2-3% bromo acids are used in lipstick Solvent

used to be mixed with bromo acids: Castor oil & butyl stearate THFA & esters like acetate, stearate & benzoate Glyceryl

monostearate or monolaurate & diethylene glycol monostearate PG or PEG

COLORS :

COLORS Most important from commercial & appearance point of view. In olden days, carmine was widely used, but

nowadays various other are available. Color in lipstick is imparted by two ways: By staining the skin with soln of dyestuff

which can penetrate the outer layer of skin ---- SOLUBLE DYES By covering the lips with a colored layer which serves to

hide any skin roughness & give a smooth appearance ---- INSOLUBLE DYES

PRESERVATIVES :

PRESERVATIVES Used to prevent microbial growth Example: 0.1% propyl parahydrohybenzoate in 0.1% Higher conc. of

preservative can cause slightly burning sensation or allergic reaction.

FRAGRANCE :

FRAGRANCE Essential component of lipstick Used to mask bad odor of fatty or wax Used to impart attractive flavor Conc.

2-4% Qualities for selection: Free from irritating effect Free from disagreeable taste Stable & compatible with other ings.

ANTIOXIDANTS :

ANTIOXIDANTS Incorporated to prevent rancidification of oily base during storage. Generally used in combination

Example: BHA, BHT, Propyl gallate, Citric acid

SURFACTANTS & OTHER ADDITIVES :

SURFACTANTS & OTHER ADDITIVES SURFACTANTS :Used to promote wetting & stabilize the dispersion of insoluble

pigments in lipstick base ADDITIVES: used for various purposes Oil - soluble sunscreen: filter the sunrays & protect lip skin

from sun burn. Silicon fluid: used as fixative & prevent colors, from bleeding on lips. PVP: (conc. 0.5 – 1%) film former on

lips & reduce allergic reaction of other ings. in lipstick. Isopropyl linoleate: prevent drying effect.

Evaluation Parameters

Melting point

Lipstick sample of 50 mg was taken. This was melted and filled into a glass capillary tube open on both the ends. This

capillary tube was cooled in ice for about 2 h and fastens it to a thermometer. This assembly was dipped into a beaker full of

water and was heated with a continuous stirring. The temperature at which the material moves along the capillary tube was

considered its melting point.

Softening point (ring and ball method)

The lipstick sample was inserted in to an aluminum ring. Extra mass above and below the orifice was removed using a sharp

blade to get a lipstick tablet in to the ring. This was placed in a refrigerator (6°C) for 10 min. After removing it from the

refrigerator, the ring was fastened onto a stand and a steel ball was delicately placed on the lipstick tablet. This assembly was

dipped in to a beaker full of water. This was heated with a continuous stirring. Temperature was monitored using a

thermometer. Softening point was the temperature at which both the lipstick mass and the steel ball were loosened and falls to

the bottom of the beaker.

Breaking load test

The protruded lipstick salve was subjected to a number of weights hanging from it. The weight at which the lipstick breaks

was its breaking load.

Stability studies

The lipsticks were placed for stability studies at temperature 4°C, 20-25°C, 30-40°C and were observed for effects like

sweating, bleeding, streaking, and blooming.

Permeation studies

Lip membrane from freshly slaughtered cattle was recovered and washed for removing adhering matter and tissues. The same

was placed on the diffusion cell, and 50 mg of lipstick mass was applied on the membrane. This was magnetically stirred (600

rpm); receiving phase was isotonic, pH 6.4 phosphate buffer. The experimental temperature was maintained at 32°C by

circulation of thermostated water inside the cell jacket. Sampling was done at 1-h interval and analyzed under UV at 220 nm

for 8 h.

Standardization

Calibration curve of drug was made using UV spectrophotometry in phosphate buffer pH 6.4; 500 µ g/ml stock solution of

allantoin was made in phosphate buffer pH 6.8. The absorbance was recorded at lmax of 220 nm.

rancidity:

rancidity Rancidification is the decomposition of fats, oils and other lipids by hydrolysis or oxidation Is the oxidation of

castor oil or other waxy or lipoidal ingredients It leads to obnoxious odor, bad taste & sticky product & sometimes change of

colour of the product Testing of rancidity can be done by determinig its peroxide number.

The Manufacturing

Process

The manufacturing process is easiest to understand if it is viewed as three separate steps: melting and mixing the lipstick;

pouring the mixture into the tube; and packaging the product for sale. Since the lipstick mass can be mixed and stored for later

use, mixing does not have to happen at the same time as pouring. Once the lipstick is in the tube, packaging for retail sale is

highly variable, depending on how the product is to be marketed.

Melting and mixing

1 First, the raw ingredients for the lipstick are melted and mixed—separately because of the different types of

ingredients used. One mixture contains the solvents, a second contains the oils, and a third contains the fats and waxy

materials. These are heated in separate stainless steel or ceramic containers.

2 The solvent solution and liquid oils are then mixed with the color pigments.

After the pigment mass is prepared, it is mixed with the hot wax. The mixture is agitated to free it of any air bubbles.

Next, the mixture is poured into tubing molds, cooled, and separated from the molds. After final touch-up and visual

inspection, the lipstick is ready for packaging.

mixture passes through a roller mill, grinding the pigment to avoid a "grainy" feel to the lipstick. This process

introduces air into the oil and pigment mixture, so mechanical working of the mixture is required. The mixture is

stirred for several hours; at this point some producers use vacuum equipment to withdraw the air.

3 After the pigment mass is ground and mixed, it is added to the hot wax mass until a uniform color and consistency is

obtained. The fluid lipstick can then be strained and molded, or it may be poured into pans and stored for future

molding.

4 If the fluid lipstick is to be used immediately, the melt is maintained at temperature, with agitation, so that trapped

air escapes. If the lipstick mass is stored, before it is used it must be reheated, checked for color consistency, and

adjusted to specifications, then maintained at the melt temperature (with agitation) until it can be poured.

As expected, lipsticks are always prepared in batches because of the different color pigments that can be used. The

size of the batch, and the number of tubes of lipstick produced at one time, will depend on the popularity of the

particular shade being produced. This will determine the manufacturing technique (automated or manual) that is used.

Lipstick may be produced in highly automated processes, at rates of up to 2,400 tubes an hour, or in essentially manual

operations, at rates around 150 tubes per hour. The steps in the process basically differ only in the volume produced.

Molding

5 Once the lipstick mass is mixed and free of air, it is ready to be poured into the tube. A variety of machine setups are

used, depending on the equipment that the manufacturer has, but high volume batches are generally run through a

melter that agitates the lipstick mass and maintains it as a liquid. For smaller, manually run batches, the mass is

maintained at the desired mix temperature, with agitation, in a melter controlled by an operator.

6 The melted mass is dispensed into a mold, which consists of the bottom portion of the metal or plastic tube and a

shaping portion that fits snugly with the tube. Lipstick is poured "up-side down" so that the bottom of the tube is at the

top of the mold. Any excess is scraped from the mold.

7 The lipstick is cooled (automated molds are kept cold; manually produced molds are transferred to a refrigeration

unit) and separated from the mold, and the bottom of the tube is sealed. The lipstick then passes through a flaming

cabinet (or is flamed by hand) to seal pinholes and improve the finish. The lipstick is visually inspected for air holes,

mold separation lines, or blemishes, and is reworked if necessary.

8 For obvious reasons, rework of the lipstick must be limited, demonstrating the importance of the early steps in

removing air from the lipstick mass. Lipstick is reworked by hand with a spatula. This can be done in-line, or the tube

can be removed from the manufacturing process and reworked.

Manufacture

The manufacturing processes should meet the requirements of Good Manufacturing Practice. The following information is

intended to provide very broad guidelines concerning the main steps to be followed during production, indicating those that

are the most important.

Throughout manufacturing, certain procedures should be validated and monitored by carrying out appropriate in-process

controls. They should be designed to guarantee the effectiveness of each stage of production. Appropriate limits should be set

for the particle size of the active ingredient(s), which should be controlled during production. Particular care should be paid to

environmental conditions, especially with respect to microbial and cross-contamination.1

1 Warning: Semi-solid dosage forms should not be diluted. If a dilution is nevertheless necessary, this requires special

attention; the same type of base should be used in order to obtain a homogeneous mixture.

Packaging must be adequate to protect topical semi-solid dosage forms from light, moisture, and damage due to handling and

transportation. The use of flexible tubes of suitable metal or plastic is preferred. Preparations for nasal, aural, vaginal, or rectal

use should be supplied in containers adapted for appropriate delivery of the product to the site of application, or should be

supplied with a suitable applicator.

EVALUATION OF OINTMENTS

Penetration

Rate of release of medicament

Absorption of medicament in blood stream

Irritant effect

Penetration

A weighed quantity of ointment is rubbed over skin for a given period of time and unabsorbed ointment is collected and

weighed.

The differences in weights represent the amount absorbed.

RATE OF RELEASE OF MEDICAMENT

If the medicament is bactericidal the agar plate is previously seeded with a suitable organism like s.aureus. After a

suitable period of incubation, the zone of inhibition is measured and correlated with the rate of release. Another method for

finding out release rate is to smear internal surface of test tubes with thin layers of ointment, fill the tubes with saline/serum

and after a gap of time estimating the amount of drug present in the serum/saline

ABSORPTION OF MEDICAMENT INTO BLOOD STREAM

The diadermatic ointment should be evaluated for the rate of absorption of drug into the blood stream. This test can be

run in-vivo only.

Definite amount of ointments should be rubbed through the skin. Under standard conditions and medicaments are

estimated in the blood plasma or urine.

IRRITANT EFFECT

The irritant effect can also be judged to a certain extent by injecting the ointment into thigh muscles and under the

abdominal skin of rats. Reaction are noted at intervals of 24,48,72 and 96 hours. Lesions on cornea, iris, conjunctiva

are used for judging the irritancy to the eyes. Presence of patches on the skin within 2 weeks indicate irritancy to

pressing skin.

Rheology

Rheologic measurements are utilized to characterize the ease of pouring from a bottle, squeezing from a tube or other

deformable container, maintaining product shape in a jar or after extrusion rubbing the product onto and into the skin and

pumping the product from mixing and storage to filling equipment.

Effect of Vehicles : Viscosity pH volatility

D) Effect of Additives : Surfactants Humectants Penetration enhancers

Yield Value It is a measure of the force required to extrude the material from the deformable bottle tube. It can be determined

by the use of an instrument called the Penetrometer. Penetrometer consist of a metal needle that pierces through the system

and the distance of penetration of the needle is measured, from which the yield value may be calculated.

Spreadability The Spreadability test is performed to determine the extent of Spreadability of gels based on their rheological

properties. Stability This test is known as the shipping test and is performed to determine the extent of stability of gels at

varying temperature, which the product may experience while exporting to other countries. Safety The safety of the product

on use should be determined in order to check the effect of the product by evaluating the physiological properties of the raw

materials.

PASTES Pastes are the preparations contain a large amount of finely powdered solids such as starch and zinc oxide. These are

generally very thick and stiff.

LAMINAR AIR FLOW

LAF

when fresh air is passed in the laminar air flow it replaces the comtamintaed air inside and keeps it contamination free.

PRINCIPAL- Laminar Air Flow is based on the flow of air current to create uniform velocity, along parallel lines, which

helps in transforming microbial culture in aseptic conditions .

PRINCIPLE

The Laminar Air Flow Cabinets are based on the principle

to provide a work area completely bathed in a high efficiency

perfect air, which is free from any kind of particulate contamination or impurities.

HORIZONTAL Laminar air flow are clean benches which have their own supply of highly purified air in which the total air

present in the

enclosure moves in a unit directional velocity flowing in parallel lines, which is free from macroscopic fluctuations. The

horizontal laminar

air flow units directs the air in mono direction which is away from the specimen and towards the user, giving ultimate

protection to the

product, which is susceptible to contamination induced by diffusion of contaminated air carrying air transported contaminants

from the outside environment.

1. Provide clean air to the working area.

2. Provide a constant flow of air out of the work area to prevent room air from entering.

3. The air flowing out from the hood suspends and removes contaminants introduced into the work area by personnel.

The most important part of a laminar flow hood is a high efficiency bacteria-retentive filter. Room air is taken into the unit

and passed through a pre-filter to remove gross contaminants (lint, dust etc). The air is then compressed and channeled up

behind and through the HEPA filter (High Efficiency Particulate Air filter) in a laminar flow fashion--that is the purified air

flows out over the entire work surface in parallel lines at a uniform velocity. The HEPA filter removes nearly all of the

bacteria from the air.

The environmental control of air is of concern because room air may be highly contaminated. Example: Sneezing produces

100,000 - 200,000 aerosol droplets which can then attach to dust particles. These contaminated particles may be present in the

air for weeks. (Have you ever viewed the air around you when you open the curtains on a sunny day?)...

Limitations: With poor technique it is easy to overcome the established airflow velocity and introduce reverse currents that

can re-introduce contaminants into the work area. Laminar hoods should remain on 24 hours a day. If turned off for any

reason, it should be on for at least 30 minutes and thoroughly cleaned before reusing.

Ophthalmic preparations

Definition: They are specialized dosage forms designed to be instilled onto the external surface of the eye (topical), administered inside (intraocular) or adjacent (periocular) to the eye or used in conjunction with an ophthalmic device.

The most commonly employed ophthalmic dosage forms are solutions, suspensions, and ointments.

these preparations when in­stilled into the eye are

rapidly drained away from the ocular cavity due to tear flow and lacrimal nasal drainage.

The newest dosage forms for ophthalmic drug delivery are: gels, gel­forming solutions, ocular inserts , intravitreal injections and implants.

Drugs used in the eye:

• Miotics e.g. pilocarpine Hcl • Mydriatics e.g. atropine • Cycloplegics e.g. atropine • Anti­inflammatories e.g. corticosteroids • Anti­infectives (antibiotics, antivirals and antibacterials)

• Anti­glucoma drugs e.g. pilocarpine Hcl • Surgical adjuncts e.g. irrigating solutions • Diagnostic drugs e.g. sodiumfluorescein • Anesthetics e.g. tetracaine

Anatomy and Physiology of the

Eye:

• The sclera: The protective outer layer of the eye, referred to as the “white of the eye” and it maintains the shape of the eye.

• The cornea: The front portion of the sclera, is transparent and

allows light to enter the eye. The cornea is a powerful refracting surface, providing much of the eye's focusing power.

• The choroid is the second layer of the eye and lies between the

sclera and the retina. It contains the blood vessels that provide nourishment to the outer layers of the retina.

• The iris is the part of the eye that gives it color. It consists of

muscular tissue that responds to surrounding light, making the pupil, or circular opening in the center of the iris, larger or smaller depending on the brightness of the light.

• The lens is a transparent, biconvex structure, encased in a thin transparent covering. The function of the lens is to refract and focus incoming light onto the retina.

• The retina is the innermost layer in the eye. It converts

images into electrical impulses that are sent along the optic nerve to the brain where the images are interpreted.

• The macula is located in the back of the eye, in the

center of the retina. This area produces the sharpest vision.

• The inside of the eyeball is divided by the lens into two fluid­filled

sections.

• The larger section at the back of the eye is filled with a colorless

gelatinous mass called the vitreous humor.

The smaller section in the front contains a clear, water­ like material

called aqueous humor. • The conjunctiva is a mucous membrane that begins at the edge

of the cornea and lines the inside surface of the eyelids and

sclera, which serves to lubricate the 6

eye.

Absorption of drugs in the eye:

Factors affecting drug availability:

1­ Rapid solution drainage by gravity, induced lachrymation, blinking reflex, and normal tear turnover:

­ The normal volume of tears = 7 µl, the blinking eye can

accommodate a volume of up to 30 µl without spillage,

the drop volume = 50 ul

lacrimal nasal drainage:

2­ Superficial absorption of drug into the conjunctiva and sclera and rapid removal by the peripheral blood flow

3­ Low corneal permeability (act as lipid barrier)

General safety considerations

A. Sterility

­ Ideally, all ophthalmic products should be terminally sterilized in the final packaging.

­ Only a few ophthalmic drugs formulated in simple

aqueous vehicles are stable to normal autoclaving temperatures and times (121°C for 20­30 min).

*Such heat­resistant drugs may be packaged in glass or other heat­deformation­resistant packaging and thus can be sterilized in this manner.

­

Most ophthalmic products, however cannot be heat

sterilized due to the active principle or polymers used to

increase viscosity are not stable to heat.

Most ophthalmic products are aseptically manufactured and

filled into previously sterilized containers in aseptic

environments using aseptic filling-and-capping techniques

B. Ocular toxicity and irritation ­ Albino rabbits are used to test the ocular toxicity and

irritation of ophthalmic formulations. ­ The procedure based on the examination of the

conjunctiva, the cornea or the iris. ­ E.g. USP procedure for plastic containers:

1­ Containers are cleaned and sterilized as in the final

packaged product.

2­ Extracted by submersion in saline and cottonseed oil.

3­ Topical ocular instillation of the extracts and blanks in

rabbits is maintained and ocular changes examined.

C. Preservation and preservatives • Preservatives are included in multiple­dose eye solutions for

maintaining the product sterility during use. • Preservatives not included in unit­dose package. • The use of preservatives is prohibited in ophthalmic products that

are used at the of eye surgery

So these products should be packaged in sterile, unit-of-use

containers.

• The most common organism is Pseudomonas aeruginosa that

grow in the cornea and cause loss of vision.

Examples of preservatives:

1- Cationic wetting agents:

• Benzalkonium chloride (0.01%)

• It is generally used in combination with 0.01­0.1% disodium edetate (EDTA). The chelating, EDTA has the ability to render the resistant strains of PS aeruginosa more sensitive to benzalkonium chloride.

2­ Organic mercurials:

• Phenylmercuric nitrate 0.002­0.004%

phenylmercuric acetate 0.005­0.02%.

3-Esters of p-hydroxybenzoic acid:

• Mixture of 0.1% of both methyl and propyl

hydroxybenzoate (2:1)

4- Alcohol Substitutes:

• Chlorobutanol(0.5%). Effective only at pH 5-6. • Phenylethanol (0.5%)

Ideal ophthalmic delivery system

Following characteristics are required to optimize

ocular drug delivery system:

• Good corneal penetration. • Prolong contact time with corneal tissue. • Simplicity of instillation for the patient. • Non irritative and comfortable form • Appropriate rheological properties

Classification of ocular drug delivery

systems

­Solutions ­Ointments

­ Ocular inserts

­ Suspensions ­ Gels

­ Powders for

reconstitution

­ Sol to gel system

A. Topical Eye drops:

1- Solutions

­ Ophthalmic solutions are sterile solutions, essentially free

from foreign particles, suitably compounded and

packaged for instillation into the eye.

19

2- suspensions

3- Powders for Reconstitution

4­ Gel-Forming Solutions

redients in Topical Drops

1- Tonicity and Tonicity-Adjusting Agents

2- pH Adjustment and Buffers

• pH adjustment is very important as pH can:

1­ render the formulation more stable

2­ improve the comfort, safety and activity of the

product. 3­ enhance aqueous solubility of the drug.

4­ enhance the drug bioavailability

5­ maximize preservative efficacy

3­ Stabilizers & Antioxidants

4­ Surfactants

27

5- Viscosity-Imparting Agents

(to retard the rate of

setting of particles)

6- Vehicles

Packaging

• Eyedrops have been packaged almost entirely in plastic dropper bottles (the Drop-Tainer® plastic dispenser).

• The main advantage of the Drop-Tainer are:

- convenience of use by the patient - decreased contamination potential - lower weight - lower cost

• The plastic bottle and dispensing tip is made of low-density polyethylene (LDPE) resin, which provides the necessary flexibility and inertness.

• The cap is made of harder resin than the

bottle.

• Packaging

(By autoclaving or by ethylene oxide)

C. Ocular Inserts

Insoluble inserts

• Insoluble insert is a multilayered structure consisting of a drug containing core surrounded on each side by a layer of copolymer membranes through which the drug diffuses at a constant rate.

• The rate of drug diffusion is controlled by:

­ The polymer composition ­ The membrane thickness ­ The solubility of the drug

e.g. The Ocusert® Pilo-20 and Pilo-40 Ocular system

­ Designed to be placed in the inferior cul­de­sac between the sclera and the eyelid and to release pilocarpine continuously at a steady rate for 7 days for treatment of glucoma.

- consists of (a) a drug reservoir, pilocarpine (free base), and a carrier material, alginic acid: (b) a rate controller ethylene vinyl acetate (EVA) copolymer membrane.

D. Intraocular Dosage Forms • They are Ophthalmic products that introduced into the

interior structures of the eye primarily during ocular

surgery. • Requirements for formulation:

1­ sterile and pyrogen­free

2­ strict control of particulate matter

3­ compatible with sensitive internal tissues

4­ packaged as preservative­free single dosage

1- Irrigating Solutions

• It is a balanced salt solution was developed for

hydration and clarity of the cornea during surgery.

2- Intraocular Injections

3- Intravitral Implant

DEFINATION:

Parenteral refers injectable route of administration.

It derived from Greek words PARA (Outside) and ENTERON (Intestine). So

it is a route of administration other than the oral route. This route of

administration bypasses the alimentary canal

Pyrogens, fever-producing substances are primarily lipid polysaccharide

product of metabolism of microorganism; they may be soluble,

insoluble, or colloid.

Parenteral Dose Forms

• Parenteral preparations must be sterile – free of microorganisms

• To ensure sterility, parenterals are prepared using – aseptic techniques

– special clothing (gowns, masks, hair net, gloves)

– laminar flow hoods placed in special rooms

Advantages of the Parenteral Route • The IV route is the fastest method for delivering systemic drugs

– preferred administration in an emergency situation • It can provide fluids, electrolytes, and nutrition

– patients who cannot take food or have serious problems with the GI tract

• It provides higher concentration of drug to bloodstream or tissues

– advantageous in serious bacterial infection • IV infusion provides a continuous amount of needed medication

– without fluctuation in blood levels of other routes • infusion rate can be adjusted

– to provide more or less medication as the situation dictates

Drug action can be prolonged by modifying the formulation.

Disadvantages of the Parenteral Route • Traumatic injury from the insertion of needle • Potential for introducing:

– Toxic agents

– Microbes

– Pyrogens • Impossible to retrieve if adverse reaction occurs

– injected directly into the body • Correct syringe, needle, and technique must be used • Rotation of injection sites with long-term use

– prevents scarring and other skin changes

– can influence drug absorption

Routes of Administration of parenteral products

Various types of route of administration of parenteral products are: Intradermal injection

Subcutaneous (Hypodermis) injection

Intramuscular injection

Intravenous injection

Intra-arterial injection

Intracardiac injection

Intrathecal injection

Intracisternal injection

Peridural injection

Intra- articular injection

Intracerebral injection

Subcutaneous Injections • Administer medications below the skin into the subcutaneous fat outside of

the upper arm top of the thigh lower portion of each side of the abdomen not into grossly adipose, hardened, inflamed, or swollen tissue

­ Often have a longer onset of action and a longer duration of action compared

with IM or IV injection ­ Given at a 45-degree angle

– 25- or 26-gauge needle, 3/8 to 5/8 inch length

­ No more then 1.5 ml should be injected into

the site

– to avoid pressure on sensory nerves causing pain and discomfort

Intramuscular Injections

• Care must be taken with deep IM injections to avoid hitting a vein, artery, or nerve

• In adults, IM injections are given into upper, outer portion of

the gluteus maximus – large muscle on either side of the buttocks

• For children and some adults, IM injections are given into the

deltoid muscles of the shoulders • Typical needle is 22- 25 gauge ½- to 1-inch needle

• IM injections are administered at a 900 angle

volume limited to less than 3 ml

Intravenous Injections or Infusions

• Fast-acting route because the drug goes directly into the bloodstream – often used in the emergency department and in critical care

areas • Commonly used

– for fluid and electrolyte replacement

– to provide necessary nutrition to the patient who is critically ill • Intravenous (IV) injections are

administered at a 15- to 20-degree

angle

Intra-arterial injection

The inaction are given directly in to the artery

Intracardiac injection

These are given into the heart muscle or ventricle at the time of emergency only.

Intrathecal injection

These are given into the subachonoid space the surround the spinal cord. This route is used for spinal anesthesia.

Intracisternal injection

These are given in b/w first & second cervical nerve.

Used for CSF for diagnostic purpose.

Peridural injection

These are given in b/w the dura matter & inner aspectof vertebra.

Used for given spinal anesthesia.

Intra- articular injection

These are given in into the articulating ends of bones in a joint.

Used for lubricating the joints.

Intracerebral injection

These are given into the cerebrum.

Official types of injections

• Injection: Liquid preparation there are drug substance drug solution thereof e.g. insulin injection USP.

• For injection: Dry solid that upon addition of suitable vehicles yield solutions confirming in all respect to the requirements to the injection. e.g. Cefuroxime injection USP.

• Injectable emulsions: Liquid preparation of drug substance dispersed in a suitable emulsion medium. e.g. Propofol USP.

• Injectable suspension: Liquid preparation of solid suspended in a suitable medium. e.g. Methyl Prednisolone Acetate Suspension USP.

• For injectable suspension: Dry solid that upon addition of suitable vehicle yields preparation confirming in all respect

to the requirements for Injectable suspension.

e.g. Imipenem and Cilastatin injectable suspension USP. 11

General requirements of parenteral preparations

Stability

Sterility

Free from Pyrogens

Free from foreign particles

Isotonicity

Specific gravity

Chemical purity

Formulation of parenteral products • In the preparation of parenteral products, the following substances are added to

make a stable preparation: The active drug

Vehicles Aqueous vehicle(e.g. water for injection, water for injection free from CO2) Non-aqueous vehicle(e.g. Ethyl alcohol, propylene glycol, almond oil)

Adjuvants

Solubilizing agents(e.g. Tweens & polysorbates) Stabilizers & antioxidants(e.g. thiourea, ascorbic acid, tocopherol) Buffering agents(e.g. citric acid, sodium citrate) Antibacterial agents(e.g. benzyl alcohol, metacresol, phenol) Chelating agents(e.g. EDTA)

Suspending, emulsifying & wetting agents(e.g. MC, CMC)

Tonicity factor(e.g. sodium chloride, dextrose)

PREFORMULATION FACTORS • It is study about physical & chemical properties of drug substance prior

formulation is called as preformulation. • They are

• pH /pka

• Solubility

• Thermal/heat effect

• Dissociation constant

• Compatabilty studies- FTIR / DSC

• Oxidation & reduction

• particle size

pH and pKa SOLUBILITY PROFILE • pKa Determination: The Henderson – Hasseslebach equation

provides an estimate of the ionized and un ionized durg concentration

at a particular pH.

For acidic drugs,

pH = pKa + log (ionized drug) / un-ionized drug) For

basic drugs,

pH = pKa + log (unionized drug / ionized drug ) - Buffers, temperature, ionic strength and cosolvent can affect the pKa value. - Potentiometric titration offers maximum sensitivity for

compounds with pKa values in the range of 3-10.

15

SOLUBILIZATION

• Solubilization is increased by co solvent addition. • E.g.- propylene glycol solubilize drug molecules by

disrupting the hydrophobic interactions of water.

More non polar the solute

greater is the solubilisation

achieved by co solvent addition

THERMAL/HEAT EFFECTS • Drugs which are unstable to heat requires refrigerative storage or

lyophilisation (these products must be used within short periods) • If it is endothermic ---> ∆H is +

ve

increase in temp ---> increase in drug solubility ­ If it is exothermic ---> ∆H is – ve

increase in temp ---> decrease in drug solubility • For determining ∆H

ln S= - ∆H /RT + C

S=molar solubility at temperature, T=temperature in Kelvin,

R= gas constant 17

PARTICLE SIZE

­ FINE PARTICLE CHARACTERISATION Very imp. Property and

here smallest particle should be tested to facilitate homogeneous

sample preparation. ­ Coulter Counter Technique To check particle size and particle volume ­ BET (BRUNAUER, EMMET, TELLER) NITROGEN

ADSORPTION APPARATUS Measurement of surface area

­ SEM( SCANNING ELECTRON MICROSCOPY) to check surface

morphology

OXIDATION & REDUCTION

• Adding oxygen to form an oxide (oxidation) or 2H2 + O2 -> 2H2O

• Removing oxygen (reduction). • Due to oxidation ,

shelf life reduces

E. changes in color

F. Potency of drug becomes less

So antioxidants are used to prevent oxidation e.g sodium bisulphate,

sodium metabisulphate

Processing of parenteral preparation

Following steps are involved in the processing of parenteral preparation:

1) Cleaning of containers, closures & equipments

2) Collection of materials

3) Preparation of parenteral products

4) Filtration

5) Filling the preparation in final container

6) Sealing the container

7) Sterilization

8) Evaluation of the parenteral preparation

9) Labeling & packaging 20

1. Cleaning of containers, closures & equipments: Thoroughly cleaned with detergents with tap water distilled water finally rinsed with water for injection.

Rubber closures are washed with 0.5% sod. pyrophosphate in water.

2. Collection of materials: All raw material of preparation should be collect from warehouse after accurate weighed. Water for injection should be Pyrogens free.

3. Preparation of parenteral products: The parenteral preparation must

be prepared in aseptic conditions.

The ingredients are accurately weighed separately and dissolved in vehicle as per method of preparation to be followed.

4. Filtration: The parenteral preparation must be filtered by bacteria proof filter such as, filter candle, membrane filter.

5. Filling the preparation in final container: The filling operation is carried out under strict aseptic precautions.

6. Sealing the container: Sealing should be done immediate after filling

in aseptic environment. 7. Sterilization: For thermostable substances the parenteral products

are sterilized by autoclaving method at different temp. & pressure.

10 lb pressure (115.50C, or 240

0F) for 30 minutes

15 lb pressure (121.50C, or 250

0F ) for 20 minutes

20 lb pressure(126.50C, or 260

0F) for15 minutes

Heat sensitive or moisture sensitive material are sterilized by exposure to ethylene oxide or propylene oxide gas .

8. Evaluation of the parenteral preparation: The following tests are performed in order to maintain quality control:

1. Sterility test 2. Clarity test 3. Leakage test

4. Pyrogen test 5. Assay

Evaluation of Parenteral products

Sterility testing

Particulate matter monitoring

Faculty seal packaging or leakage test

Pyrogen testing

LAL test

Assay or drug content uniformity

Sterility testing • DEFINITION: Sterility Testing: It is a procedure carried out to detect conform absence of any

viable form of microbes in or on pharmacopeia preparation or product.

• PRINCIPLE : Sterility testing only shows that organisms capable of growing in selected

conditions are absent from the fraction of batch that has been tested. If the microorganism

are present in the product can be indicated by a turbidity in the clear medium. • OBJECTIVE OF STERILITY TESTING:

For validation of sterilization process.

To check presence of microorganisms in preparation which are sterile.

To prevent issue of contaminated product in market. 24

• STEPS INVOLVED IN STERILITY TE TESTING

1) Sampling

2) Selection of the quantity of the product to be used

3) Method of sterility testing

i ) METHOD 1 Membrane filtration method

ii) METHOD 2 Direct inoculation method

4) Observation and interpretation Must be carried out under

aseptic condition.

Sampling

• The sample must be representative of the whole of the bulk material

& a lot of final containers. • MAINLY FOLLOWED BY TWO RULES:

A fixed percentage of the final container are selected.

A fixed number of container are taken independent of the lot

or batch size.

According to Indian Pharmacopoeia following guidelines for determining the minimum number of items are:

Selection of the quantity of the product to be used

• Selection of the quantity of the product to be used for sterility testing

depends mainly on the volume or weight in the container.

Method of sterility testing

Membrane filtration method (METHOD 1):

Membrane filtration Appropriate for : (advantage)

– Filterable aqueous preparations

– Alcoholic preparations

– Oily preparations

– Preparations miscible with or soluble in aqueous or oily (solvents

with no antimicrobial effect)

All steps of this procedure are performed aseptically in a Class 100

Laminar Flow Hood

Membrane filter 0.45μ porosity

Filter the test solution

After filtration remove the filter

Cut the filter in to two halves

First halves (For Bacteria) Second halves (For Fungi)

Transfer in 100 ml culture media Transfer in 100 ml culture media

(Fluid Thioglycollate medium) (Soyabeans-Casein Digest medium)

Incubate at 30-350 C for not less then 7 days Incubate at 20-250 C for not less then 7 days Observe the growth in the media Observe the growth in the media29

Direct inoculation method (METHOD 2):

Suitable for samples with small volumes

volume of the product is not more than 10% of the volume of the medium

suitable method for aqueous solutions, oily liquids, ointments an creams

Direct inoculation of the culture medium suitable quantity of the preparation to be examined is transferred directly into the appropriate culture medium & incubate for not less than 14 days.

Observation and results Culture media is examined during and after at the end of incubation.

The following observations are possible:

1) No evidence of growth Pass the test for sterility.

2) There is evidence of growth Re-testing is performed same no.

of sample, volume & media as in original test No evidence of

growth Pass the test for sterility.

3) There is evidence of growth isolate & identify the organism.

Re-testing is performed with twice no. of sample if:

No evidence of growth Pass the test for sterility.

There is evidence of growth Fail the test for sterility

Particulate matter monitoring • Particulate matter is defined as unwanted mobile insoluble matter other

than gas bubble present in the product. • If the particle size of foreign matter is larger than the size of R.B.C.. It can

block the blood vessel. • The permit limits of particulate matter as per I.P. are follows: Source of particulate matter:

1. Intrinsic contamination: The material which are originally present in the parenteral solution e.g. Barium ions leach in parenteral & react with sulphur ions in the product to form barium sulphate crystals.

2. Extrinsic contamination: The material which comes from the environment e.g. Shedding of material from cloth, body, &

cotton, paper, rubber, tissue etc. 32

Methods for monitoring particulate matter contamination:

1) Visual method 2) Coulter counter method 3) Filtration method 4) Light blockage method

Identification of particulate matter:

1) Microscopy 2) X-ray powder diffraction 3) Mass spectroscopy 4) Polarized light spectroscopy 5) Scanning electron microscopy (SEM)

Faculty seal packaging / leaking testing • The sealed ampoules are subjected to small cracks which occur to rapid

temperature changes or due to mechanical shocks.

Filled & sealed ampoules

Dipped in 1% Methylene blue solution

Under negative pressure in vacuum chamber

Vacuum released colored solution enter into the ampoule

Defective sealing • Vials & bottles are not suitable for this test because the sealing material used is not

rigid.

Pyrogen Testing Pyrogen =P ro(Greek =Fire) +ge(Greek =beginning). Fever producing, metabolic by-products of microbial growth and death.

Bacterial pyrogens are called E doto i s . Gram negative bacteria produce more potent endotoxins than gram + bacteria and fungi.

Endotoxins are heat stable lipopolysaccharides (LPS) present in bacterial cell walls, not present in cell-free bacterial filtrates

Stable to at least 175oC; steam sterilization ineffective Water soluble; monomer unit of LPS can be 10,000 Daltons (1.8 nm)

so endotoxins can easily pass through 0.22μ filters Sources: Water (main), raw materials, equipment, process environment,

people, and protein expression systems if using gram negative bacteria.

• Biological properties of endotoxin

Pyrogen elevate the circulatory levels of inflammatory cytokines which

may be followed by fever, blood coagulation, hypotension

Low doses of Pyrogen:asymptomatic inflammation reaction

Moderate doses: fever & changes in plasma composition

High doses: cardiovascular dysfunction, vasodilation, vasoconstriction,

endothelium dysfunction, multiple organ failure & finally death.

• Sources of pyrogen 1) Equipment 2) Containers (Glass , plastic , metal) 3) Solvent 4) Solute

Elimination of pyrogens

Dry heat sterilization : For glass wares, metal equipments, powders, waxes, oils,

heat stable drugs 650 250 180

o o o

C temp - 1 min C temp - 30 min C temp - 240 min

Ultra filtration

Reverse osmosis : RO membrane is composed of cellulose acetate phthalate/

polyamide

Distillation Adsorption method

• Principal:

Rabbits are used to perform this test because their body temp increases when pyrogen are introduced into their bodies by parenteral route

3 healthy adult rabbits of either sex, each weighing NLT 1.5 kg are selected

Do not use any rabbit

having a temp higher than 39.8oC

Showing temp variation >0.2oC between two successive

readingin the determination of initial temp

Sham test is performed within 7 days of actual test

Animal showing temp increase over 0.6 o C should be removed from

pyrogen testing

• Method : Dissolve the subs being examined in, or dilute it with a pyrogen free saline

solution

Warm the liquid being examined to approx. 38.5o C temp before injection

The volume of injection is NLT 0.5ml/kg & NMT 10ml/kg of body weight

Withhold water during test

Clinical thermometer is inserted into the rectum of rabbit to record body temp

2 normal reading of rectal temp are should be taken prior to the test injection at an interval of half an hr & its mean is calculated- initial temp

The solution under test is injected through an ear vein

Record the temp of each rabbit in an interval of 30 min for 3 hrs

The difference between initial temp & maximum temp is recorded- taken as response

• Bacterial endotoxin (LAL) test )

– To detect or quantify endotoxins of gram-ve bacterial origin

– Reagent: amoebocyte lysate from horseshoe crab (Limulus polyphemus or

Tachypleus tridentatus).

– The name of the test is also Limulus amebocyte lysate (LAL) test • Mechanism of LAL Test:

The test is based on the primitive blood-clotting mechanism of the horseshoe crab

enzymes located with the crab's amebocyte blood cells endotoxin

Initiation of an enzymatic coagulation cascade

proteinaceous gel

• Test performance (short) Avoid endotoxin contamination

– Before the test:

– interfering factors should not be present

– equipment should be depyrogenated the sensitivity of the lysate should be

known

Test:

– equal Volume of LAL reagent and test solution (usually 0.1 ml of each) are

mixed in a depyrogenated test-tube

– Incubation at 37°C, 1 hour

– remove the tube - invert at (180°) observe the result

– pass-fail test

LAL test • Three different techniques:

1. The gel-clot technique - gel formation

2. The turbidimetric technique - the development of Turbidity after cleavage of an endogenous substrate

3. The chromogenic technique - the development of color after cleavage

of a synthetic peptide- chromogen complex • Advantages of LAL test

Fast - 60 minutes vs. 180 minutesGreater Sensitivity ,Less Variability Much Less False, Positives ,Much Less ExpensiveAlternative to Animal Model, cheaper,particularly useful for:

Radiopharmaceuticals and cytotoxic agentsBlood products

Water for injection

Production facilities of parenterals

• The production area where the parenteral preparation are

manufactured can be divided into five sections:

Clean-up area

Preparation area

Aseptic area

Quarantine area

Finishing & packaging area

Clean-up area:

It is not aseptic area.

All the parenteral products must be free from foreign particles & microorganism.

Clean-up area should be withstand moisture, dust & detergent.

This area should be kept clean so that contaminants may not be carried out into aseptic area.

Preparation area:

In this area the ingredients of the parenteral preparation are mixed & preparation is made for filling operation.

It is not essentially aseptic area but strict precautions are required to prevent any contamination from outside.

Aseptic area:

The parenteral preparations are filtered, filled into final container

& sealed should be in aseptic area.

The entry of personnel into aseptic area should be limited &

through an air lock.

Ceiling, wall & floor of that area should be sealed & painted.

The air in the aseptic area should be free from fibers, dust and

microorganism.

The High efficiency particulate air filters (HEPA) is used for air.

UV lamps are fitted in order to maintain sterility.

Quarantine area:

After filling, sealing & sterilization the parenteral product are held up in quarantine area.

Randomly samples were kept foe evaluation.

The batch or product pass the evaluation tests are transfer in to finishing or packaging area.

Finishing & packaging area:

Parenteral products are properly labelled and packed.

Properly packing is essential to provide protection againstphysical damage.

The labelled container should be packed in cardboard or plastic container.

Ampoules should be packed in partitioned boxes

Lyophilization or freeze drying

• Lyophilization or freeze drying is a process in which water is removed

from a product after it is frozen and placed under a vacuum, allowing

the ice to change directly from solid to vapor without passing

through a liquid phase.

• The process consists of three separate, unique, and interdependent

processes;

– Freezing,

– Primary drying (sublimation), and

– Secondary drying (desorption).

• The advantages of Lyophilization include:

– Ease of processing a liquid, which simplifies aseptic handling

– Enhanced stability of a dry powder

– Removal of water without excessive heating of the product

– Enhanced product stability in a dry state

– Rapid and easy dissolution of reconstituted product • Disadvantages of Lyophilization include:

– Increased handling and processing time

– Need for sterile diluent upon reconstitution

– Cost and complexity of equipment

• The Lyophilization process generally includes the following steps:

– Dissolving the drug and excipients in a suitable solvent, generally water for injection (WFI).

– Sterilizing the bulk solution by passing it through a 0.22 micron bacteria-

retentive filter.

– Filling into individual sterile containers and partially stoppering the containers under aseptic conditions.

– Transporting the partially stoppered containers to the lyophilizer and

loading into the chamber under aseptic conditions.

– Freezing the solution by placing the partially stoppered containers on cooled shelves in a freeze-drying chamber or pre-freezing in another chamber.

– Applying a vacuum to the chamber and heating the shelves in order to

evaporate the water from the frozen state.

– Complete stoppering of the vials usually by hydraulic or screw rod

stoppering mechanisms installed in the lyophilizers. 49

• There are many new parenteral products,

including anti-infectives, biotechnology derived

products, and in-vitro diagnostics which are

manufactured as lyophilized products.

• Additionally, inspections have disclosed potency,

sterility and stability problems associated with the

manufacture and control of lyophilized products.

THANKYOU

BY

T.B.E.K.B