Transcript Preparation methods

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, sustainedrelease 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 acidsensitive 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
hydrophobi
area
hydrophilic
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
OR
HO
OH
O
OH
O
O
O
OH
OH
HO
OR
O
RO
HO
OR
O
HO
OH
O
O
O
RO
HO
OH
O
HO
O
O
O
OH
OH
HO
OR
β-CYD
index
Number of glucose
Mr
Internal diameter
Deep of cavity
Volume of cavity
[α]25D（H2O）
S0（g/L,25℃）
Crystal state
α-CYD
β-CYD
γ-CYD
6
7
8
973
1135
1297
0.45~0.6nm
0.7~0.8nm
0.85~1.0nm
0.7~0.8nm
0.7~0.8nm
0.7~0.8nm
17.6nm
34.6nm
51.0nm
+177.4°
+150.5°
+162.5°
145
18.5
232
needle
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
Dissolution of indomicine from common
tablets and inclusion compounds
time（min ）
I.C.
（%）
C.T.
2
4
6
8
10
15
30
45
76.1 85.2
98.2
7.2
12.00 13.4 23.5 31.3 60.3 71.8
9.2
98.0 98.5 99.2 99.2 99.7
(b)liquid drugs
avoid volatility
solid form and
(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
subnanoemulsions
A.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 tension
Formation 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 waterinsoluble 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
(hydrophobic emulsifiers)
drug-water solution
(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
polymerization
e.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. liposomes
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
A.
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
3~6
solution (drugs+water)
ultrasonic
W/O
evaporation
gels
PBS
suspension
suitable to hydrophilic drugs!
1
(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