New Technology in Drug Preparation

Chapter 16

I. Solid dispersion

A.Introduction

(1)definition: drug+vehicle

difficultly water-soluble drugs highly disperse in a solid vehicle

states of drugs: molecule, colloidal state, microcrystalline or amorphism

vehicles: water-soluble ones

water-insoluble ones

enteric-soluble ones

(2)properties

(a)increase the dissolution rate and solubility of water-insoluble drugs in order to enhance bioavailability and decrease side-effects in vivo

(b)can make quick-release, sustained-release or enteric-release preparations according to the properties of the vehicles

(c)liquid drugs solid dosage forms

(d)cover (enhance stability and reduce odor)

(d)low dosage and aging

B. Vehicles(1)water-soluble ones PEG: PEG4000, PEG6000 PVP surfactants: poloxamer, PEO,CP organic acids: unsuitable to acid-

sensitive drugs saccharide and alcohols: mannitol celluloses: HPMC, HPC

increasing solubility and dissolution rate of water-immiscible drugs

(2)water-insoluble ones

celluloses: EC

polyactylic resin: Eudragit E, RL, RS

others

sustained release

(3)enteric-soluble ones

celluloses: CAP, HPMCP, CMEC

polyactylic resin: Eudragit L, S

controlled the release site

note: compability

C. Types of solid dispersion

(1)according to the properties of vehicles

quick-release type

sustained-release type

enteric-release type

(2)according to dispersion state of drugs

eutectic mixture: microcrystalline (3)

solid solutions: molecule (1)

coprecipitates: amorphism (2)

D.preparation methods

(1)melting method drug+vehicle(m.p. low, organic solvent-insoluble)

heating

melting

freezing quickly

dosage forms

suitable to drugs and vehicles with promising heat- stability

(2)solvent method drug+vehicle organic solvent solution

evaporate the solvent

coprecipitates

dosage forms suitable to drugs with volatility or

poor stability

(3)solvent-melting method drug+solvent vehicle heating solution melting

mixing

freezing quickly

dosage forms suitable to liquid drugs with low

dosage (lower than 10%)

(4)solvent-spraying (freezing) drying

drug+vehicle

organic solvent

solution

spraying or freezing drying

solid dispersion

suitable to drugs with poor stability

equipment request

(5)others

grinding method

double-spiral extruding method

Note: (1) suitable to drugs with relative low dosage (5-20%)

(2) aging during storage (C of drug, storage conditions and properties of vehicle)

E. Mechanisms of quick- and sustained-release of solid dispersion

(1)quick-release high dispersion of drug (small size

and high energy state) enhanced by vehicles(increase

wettability, keep high dispersion, crystalline-inhibition)

(2)sustained-release water-insoluble vehicles (matrix

diffusion)

F. Identification of solid dispersion

DTA and DSC

X-ray diffraction

IR

1HNMR

dissolution rate

II. Inclusion technology

A.Definition

host molecules + guest molecules (space)

inclusion compound

molecular capsules

occlusion compound

adducts

clathrates

host molecules:

1886: hydroquinone

1916: deoxycholic acid

1940: urea

1947: sulfocarbamide

1948: cyclodextrin (CYD)

B. Types

(1)according to structure of host molecules

multi-molecule one

single-molecule one

macro-molecule one

(2)according to shape of host molecules

pipe-shape one

cage-shape one

layer-shape one

pipe cage layer

C. Mechanism of inclusion

physical combination between host and guest molecules

van der Waals attraction

Structure and polarity of guest molecules should suitable to those of host molecules!

hydrophilic area

hydrophilic area

hydrophobic area

D.CYD inclusion compound

(1)development

1891: be discovered

1948: identify the structure

before 1974: with low yield

1974: scale up and be used widely

(2)structure and properties

O

O

O

O

O

O

O

O O

O

O

O

O

OR

OH

OR

OH

OH

OH

ORHO

HO

RO

HO

HO

HO OH

OHOH

OR

OHHO

HO

RO

β-CYD

index α-CYD β-CYD γ-CYD

Number of glucose6 7 8

Mr 973 1135 1297

Internal diameter0.45~0.6nm 0.7~0.8nm 0.85~1.0nm

Deep of cavity0.7~0.8nm 0.7~0.8nm 0.7~0.8nm

Volume of cavity17.6nm 34.6nm 51.0nm

[α]25D （ H2O ）

+150.5° +162.5°+177.4°

S0 （ g/L,25℃ ）145 18.5 232

Crystal stateneedle prism prism

(3)preparation techniques

before preparation:

data analysis (possibility)

host choice (α-CYD,β-CYD,γ-CYD)

method choice (indices: yield and drug concentration)

Preparation methods:

saturated water solution method

CYD+water

saturated solution

guest

stirring and mixing

precipitate

filtrating, washing and drying

ultrasonic method mechanical stirring is replaced by

ultrasonics

grinding method CYD+2~5-fold water

paste

drying at low temperature

washing and drying

freezing-drying method

suitable to the soluble inclusion compounds and those with poor heat stability

spray-drying method

suitable to the soluble inclusion compound and those with promising heat stability

impact factors:

ratios of host and guest

preparation methods

T

stirring rate and time

drying methods

determine the optimal conditions by orthogonal experiment

(4)applications in pharmaceutics

(a)increase the dissolution rate and solubility of drugs

time （ min ） 2 4 6 8 10 15 30 45

I.C.

（ %）76.1 85.2 98.2 98.0 98.5 99.2 99.2 99.7

C.T. 7.2 9.2 12.00 13.4 23.5 31.3 60.3 71.8

Dissolution of indomicine from common tablets and inclusion compounds

(b)liquid drugs solid form and avoid volatility

(c)cover the odors of drugs and reduce irritation

Galic essential oil：

cover the odor

Chloral hydrate：

reduce the irritation to GIT

(d)enhance stability (delay oxidation, pyrolysis and photodegradation)

Vitamine D3：

60℃， 10h→0%

Vitamine D3-βCYD I.C.：

60℃， 10h→100%

(5)derivatives of CYD

water-soluble ones:

α-CYD

hydroxyethyl - β- CYD

hydroxypropyl - β- CYD

methyl - β- CYD

branched chain - CYD

poly-CYD

enhancing solubility and reducing irritation

hydrophobic ones:

ethyl - β- CYD

sustained release vehicles

(6)determination of CYD inclusion compounds

microscopy

TLC

UV

DTA and DSC

X-ray diffraction

IR

FC

1HNMR

III.Nanoemulsions and subnanoemulsionsA.Introduction(1)nanoemulsion: d 10-100nm, thermodynamic

stability system appearance high C of emulsifiers (20-30%) mix with water and oil within certain ranges low viscosity low surface tensionFormation mechanism has not been clear

completely.

(2)subnanoemulsion: d 100-500nm, better stability when compared with common emulsions while poorer stability when compared with nanoemulsion

both can be used as drug vehicles!

sustained and prolonged release!

B. Emulsifiers and coemulsifiers

(1)emulsifiers

natural ones: acacia, mucilage tragacanth, gelatine, albumin, casein, lecithin, SP, cholesterol

synthetic ones: Tweens, poloxamers, Spans

(2)coemulsifiers: n-butanol, ethylene glycol, ethanol, propylene glycol, glycerin, poly-glyceride

C.preparation of nanoemulsion

(1)formation comditions

massive emulsifiers:

20-30% of oil

adding coemulsifiers:

adjust the HLB value, insert the interfacial film, form complex agg. film, enhance the degree of rigidity and flexibility, further reduce the interfacial tension, increase the stability of nanoemulsions

(2)steps of preparation

determine the formulation:

ternary phase diagram (p358)

note: keep constant temperature

mixing according to the determined ratios

D.preparation of subnanoemulsion key instrument: high pressure emulsifier impact factors stabilizer: oleic acid enhance the strength of interfacial film increase the solubility of drug increase the absolute value of ξ

potential complex emulsifiers:

lecithin+poloxamer

E. Quality evaluation

size and size distribution

drug concentration

stability

IV. Microcapsules and microspheres (microparticles)

A.Introduction

(1)definition

polymer+drug

capsulize (membrane wall) -- microcapsules

disperse (matrix) -- microspheres

(2)properties

cover the odors of drugs

enhance the stability

liquid drugs solid

sustained or controlled release

targeting ability

B.Compositions

(1)core material

drug(s)+supplement agents

(2)coating material

natural macromolecule polymers:

gelatin, acacia, alginic acid salts, chitosan

semisynthetic macromolecule polymers:

CMC-Na, CAP, EC, MC, HPMC

synthetic macromolecule polymers:

PLA, PLGA PLA-PEG(biodegradability)

C.Preparation techniques of microcapsules(1)physical-chemical methods (p366) simple coacervation core materials 3%~5%gelatin solution

suspension or emulsion

50 ℃ adjusting pH to 3.5~3.8 by 10%HAc

60%Na2SO4

agg. capsules dilution(Na2SO4 )

sedimented capsules lower than 15 ℃ 37%formaldehyde(pH 8~9 adjusted by 20% NaOH)

solidified capsules washed by water till no formaldehyde remained

microcapsules

preparations

key: polymer solution+polycoagulant (hydrophilic)

lower solubility of polymer

suitable to water-insoluble drugs

complex coacervation: core materials 2.5%~5%gelatin+2.5%~5%acacia

suspension or emulsion

50 ~55℃ 5%HAc adjusting pH to 4.0-4.5

agg. capsules dilution(30~40 water)℃

sedimented capsules lower than 10 ℃ 37%formaldehyde(pH 8~9 adjusted by 20%

NaOH)

solidified capsules washed by water till no formaldehyde remained

microcapsules

preparations note: the differences between simple and

complex coacervation

key:

polymer with positive charge

+

polymer with negative charge

crosslinking

suitable to water-insoluble drugs

solvent-nonsolvent method:

coating material+solvent

solution

nonsolvent

lower the solubility of coating materials

phase separation

remove solvents

suitable to water-soluble and water-insoluble drugs

temperature-changing method:

EC+cyclohexane+PIB(stabilizer)

heating

solution

cooling

microcapsules

in-liquid drying:

drug+coating materials+solvent (with low m.p.)

continuous phase+emulsifiers

emulsions evaporating solvent

microcapsules

solvents: acetonitrile, acetone

continuous phase: liquid paraffin

W/O/W multiple emulsion:coating material+organic solvent drug-water solution

(hydrophobic emulsifiers) (thickening agent)

W/O

cooling,+water with

hydrophilic emulsifiers

W/O/W evaporating organic solvent

separation, drying

microcapsules

(2)physical mechanical methods

spray drying:

drug+coating material solution

solution suspension

hot inert gas

microcapsules microspheres

spray congealing:

drug dispersed in melting coating material

spraying in cold gas

coacervation

microcapsules

coating materials: waxes, fatty acid, fatty alcohol

fluidized bed coating

pan coating

multiorifice-centrifugal process

(3)chemical methods

interface polycondensation:

polycondensation occurs on the interface of the disperse phase and the continuous phase resulting in formation of microcapsules

ray-crosslinking method:

gelatin crosslinks under the -ray to form microcapsules

D.Preparation techniques of microspheres(1)gelatin microspheres emulsification crosslinking method

(2)albumin microspheres in-liquid drying, spray drying

(3)starch microshperes emulsification crosslinking method

(4)polyester microspheres in-liquid drying

(5)magnetic microspheres coprecipitation to get magnetic fluid+polymer+drugs

E. factors affecting the size of microparticles

(1)the size of core materials

(2)amount of coating materials

(3)preparation methods

(4)T

(5)stirring rate

(6)concentrations of excipients

(7)viscosity of coating material phase

F. drug release from microparticles diffusion

(1)mechanisms dissolve of coating wall

digestion and degradation of coating wall

(2)impact factors

size

thickness of coating wall

physical chemical properties of vehicles

properties of drugs

preparation conditions and dosage forms

pH of medium

ion strength of medium

G. Quality evaluation

appearance

size and size distribution

drug content

drug-loading rate

entrapment rate

release rate of drug

residual volume of organic solvents

阿糖胞苷水溶液 pH6.9，在60 ， 70 ， 80℃三个恒温水浴中进行加速实验，求得一级速度常数分别为3.50×10-4/h, 7.97×10-4/h, 1.84×10-3/h，求活化能及 t0.9

V. Nanoparticles (nanocapsules, nanospheres)

A. Properties

(1) Mean size below 100nm

(2) Targeting ability

(3) Improve stability (biomedicines: p.o.)

(4) Prolong the effective time

B. Preparation techniques(1) emulsion polymerization method monomers+water O/W+initiator polymerizatione.g. PACA nanoparticles: (pH, mean MW and C of polymer,

stabilizer, stirring rate, T, emulsifiers)

PMMA nanoparticles: (-ray or initiator, mean MW and C of

polymer, T)

(2) coacervation of natural polymers

chemical crosslinking (albumn)

heating apomorphosis (gelatin)

dehydration (polysaccharides)

(3) in-liquid drying

(4) automatic emulsification

C. Solid lipid nanosheres (SLD)

(1) Properties

high m.p. lipid as matrix

better stability

(2) Preparation methods

melting-homogenization

cold-homogenization

nanoemulsification

D. Others

magnetic nanospheres

modified nanoparticles (hydrophilic agents, MA)

E. Quality evaluation

shape

size and its distribution

entrapment rate and percolation rate

redispersibility

burst-effect (lower than 40% in the first 0.5h)

residual volume of organic solvents

VI. liposomesA. Definition

little bilayering vesicles similar to the structure of biomembrane used as drug vehicles

note: difference between liposomes and micelles

B. Types

SUVs (large and small)

MLVs

note: forming SUVs under ultrasonic condition

C. Compositions

phospholipid+cholestrol

D. Applications

simulation membrane

control drug release (targeting, sustained release, reduce toxicity, enhance stability)

vehicles for genes

E. Physical and chemical characteristics

(1) Phase transition temperature

(2) electricity: +, -, or neutrality

F. Preparation methods

(1) film dispersion method:

lipids+hydrophobic drugs+organic solvents

dissolve

solution

evaporating the solvent by rotation

film PBS (hydrophilic drugs)

hydration to get liposomes

(2) antiphase evaporation method:lipids+organic solvents solution (drugs+water)

3~6 ultrasonic 1

W/O

evaporation

gels

PBS

suspension

suitable to hydrophilic drugs!

(3) infusion method

lipids+hydrophobic drugs+ether

+PBS including hydrophilic drugs (infusion slowly)

ether evaporation (stirring)

MLVs

+high pressure emulsifier

SUVs

(4) others

freezing-drying, ultrasonic dispersion, etc

G. modified liposomes long-circulating liposomes (+hydrophilic polymers to decrease the

swallow of MPS) immunizing liposomes (+MA to improve the targeting ability) glycosyl-liposomes (+glycosyl to enhance the liver targeting) T-sensitive liposomes (depends on the phase transition of lipids) pH-sensitive liposomes (pH-sensitive lipids) magnetic liposomes, sound wave-sensitive

liposomes, etc

H. Quality evaluation

shape

size and its distribution

entrapment rate

percolation rate

oxidation of lipids

residual volume of organic solvents