Microencapsulation

“It is define has an substance or Pharmaceutical material is encapsulated over the surface of solid, droplet of liquid and dispersion of medium is known has Microencapsulation”

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Microencapsulation
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Introduction
Core Material
Coating Material
Synonyms of Microcapsules
Reasons For Microencapsulation
Release Mechanisms
Different Structures of Microcapsules
Types of Microcapsules
Application
Pharmacological & Physicochemical consideration
Classification of Microencapsulation Techniques
Applications of Microcapsules and Microspheres
Pharmaceutical Applications
Evaluation of Microencapsulation
Factors Influencing Encapsulation Efficiency
Reference
Contents

3. 33
“Microencapsulation may be defined as the process of surrounding or enveloping one substance
within another substance on a very small scale, yielding capsules ranging from less than one micron to
several hundred microns in size”
“It is define has an substance or Pharmaceutical material is encapsulated over the surface of solid,
droplet of liquid and dispersion of medium is known has Microencapsulation”
It is mean of applying thin coating to small particle of solid or droplet of liquid & dispersion.
Particle size: 50-5000 micron.
2 phases: a) Core material b) Coating material
Also known as microcapsule, microsphere, coated granules, pellets.
Introduction
Definition:
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Core Material
The material to be coated. It may be liquid or solid or gas. Liquid
core may be dissolved or dispersed material.
Composition of core material:
Drug or active constituent
Additive like diluents
Stabilizers
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Coating Material
Inert substance which coats on core with desired thickness.
Composition of coating:
Inert polymer
Plasticizer
Coloring agent
Resins, waxes and lipids
Release rate enhancers or retardants
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Synonyms of MicrocapsulesSynonyms of Microcapsules
Also known as Microcapsule, Microsphere, Microspanules,
Microsperules, Microbeads, Microballones, Microgranules,
Coated Granules, Pellets, Seeds, Spanules.
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Reasons For Microencapsulation
For sustained or prolonged drug release.
For masking taste and odor of many drugs to improve patient compliance.

For converting liquid drugs in a free flowing powder.
To reduce toxicity and GI irritation
Incompatibility among the drugs can be prevented by microencapsulation.
The drugs, which are sensitive to oxygen, moisture or light, can be stabilized by
microencapsulation
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Release Mechanisms
Degradation controlled monolithic system
Diffusion controlled monolithic system
Diffusion controlled reservoir system
Erosion
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List of coating material
Water soluble Water soluble
resinresin
Water Water
insoluble resininsoluble resin
Wax & lipidWax & lipidEnteric resinEnteric resin
Gelatin,Gelatin,
Gum Arabic,Gum Arabic,
PVP,PVP,
CMC,CMC,
Methyl cellulose,Methyl cellulose,
Arabinogalactan,Arabinogalactan,
Polyvinyl acrylate,Polyvinyl acrylate,
Polyacrylic acid.Polyacrylic acid.
Ethyl cellulose,Ethyl cellulose,
Polyethylene,Polyethylene,
PolymethacrylatesPolymethacrylates
,,
Cellulose nitrate,Cellulose nitrate,
Silicones. Silicones.
Paraffin,Paraffin,
Carnauba wax,Carnauba wax,
Bees wax,Bees wax,
Stearic acid,Stearic acid,
Stearyl alcohol.Stearyl alcohol.
Shellac,Shellac,
Zein, Zein,
Cellulose acetate Cellulose acetate
phthalate.phthalate.
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Stabilization of core material.
Inert toward active ingredients.
Controlled release under specific conditions.
Film-forming, pliable, tasteless, stable.
Non-hygroscopic, no high viscosity, economical.
Soluble in an aqueous media or solvent, or melting.
The coating can be flexible, brittle, hard, thin etc.
Coating Material Properties
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Core MaterialCharacteristic
Property
Purpose of Encapsulation Final Product
Form
Aspirin Slightly water-
soluble solid
Taste-masking; sustained release;
reduced gastric irritation;
separation of incompatibles
Tablet or capsule
Vitamin A
Palmitate
Nonvolatile liquidStabilization to oxidationDry powder
Isosorbide
dinitrate
Water soluble solid sustained release Capsule
Table 1: Properties of Some Microencapsulated Core Materials
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DIFFERENT STUCTURES OF MICROCAPSULES
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TYPES OF MICROCAPSULES
Simple Microcapsules
Enteric coated Microcapsules
Mucoadhesive Microcapsules
Bioadhesive Microcapsule
Floating Microcapsules
Magnetic Microcapsules
Nanospheres
Floating and Effervescent Microcapsules
Colonic Microspheres
GI Specific Microspheres
Intestinal Specific Microspheres
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Application
Taste masking e.g. acetaminophen.
Sustain release e.g. aspirin, iso Sorbide dinitrate.
Conversion of liquid to solid e.g. clofibrate
Odor masking e.g. castor oil, cysteine.
Reducing gastric irritation e.g. phenylbutazone.
Stabilization to oxidation e.g. vitamin
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Pharmacological & Physicochemical consideration
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Classification of Microencapsulation Techniques:Classification of Microencapsulation Techniques:
[CAMS[CAMS
22
PP
22
]]
Method Nature S/LSize Range (µ)
Coacervation phase separationS & L 2-5000
Air suspension S* 35-5000
Multiorifice centrifugal processS & L 1-5000
Solvent evaporation S & L 5-5000
Spray drying & spray congealingS & L 5-600
Pan coating S 600-5000
Polymerization technique Relatively new Technique
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Techniques To Manufacture
1. Physical methods
1.1 Air-suspension coating
1.2 Coacervation Process
1.3 Pan coating
1.4 Spray–drying
2. Chemical process
2.1 Solvent Evaporation
2.2. Polymerization
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19. Physical or Physico-mechanical methods
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1.Air-suspension coating [Fluidized Bed Dryer]
Inventions of Professor Dale E. Wurster
Basically the wurster process consists of the dispersing of solid, particulate core
materials in a supporting air stream and the spray-coating of the air suspended
particles.
Equipment ranging in capacities from one pound to 990 pounds.
Micron or submicron particles can be effectively encapsulated by air suspension
techniques. [Wurster air suspension Apparatus]
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Air-suspension
The air suspension process offers The air suspension process offers
wide variety of coating material wide variety of coating material
candidates microencapsulation.candidates microencapsulation.
It consist of dispersing the solid It consist of dispersing the solid
particulate core material in particulate core material in
supporting air stream and being supporting air stream and being
coated with coating material coated with coating material
(usually polymeric solution)(usually polymeric solution)
Disadvantage- Agglomeration of the particles to some larger size is normally
achieved.
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Processing variables for efficient, effective encapsulation by Air
Suspension techniques:
Density, surface area, melting point, solubility, friability, volatility, Crystslinity, and
flow-ability of core the core material.
Coating material concentration (or melting point if not a solution).
Coating material application rate.
Volume of air required to support and fluidizes the core material.
Amount of coating material required.
Inlet and outlet operating temperatures.
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2. Coacervation phase separation
The general process consist of 3 steps under continuous agitation:The general process consist of 3 steps under continuous agitation:
1.1.Formation of 3 immiscible chemical phaseFormation of 3 immiscible chemical phase
2.2.Deposition of coatingDeposition of coating
3.3.Rigidization of coatingRigidization of coating
Step:Step: Three immiscible phases are as:Three immiscible phases are as:
a) Liquid manufacturing vehicle phase a) Liquid manufacturing vehicle phase
b) Core material phaseb) Core material phase
c) Coating material phasec) Coating material phase
Coating material phase formed by utilizing following methods:Coating material phase formed by utilizing following methods:
Temperature changeTemperature change
By addition of incompatible polymerBy addition of incompatible polymer
By non-solvent additionBy non-solvent addition
By salt additionBy salt addition
Polymer-polymer interactionPolymer-polymer interaction04/06/16 sagar kishor savale

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(a) Core material dispersion in solution of shell polymer;
(b) separation of Coacervation from solution;
(c) coating of core material by micro droplets of coacervate;
(d) coalescence of coacervate to form continuous shell around core particles.
Fig: Schematic representation of the Coacervation process.
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Temperature change
•Core material: N-acetyl p-aminophenol
•Polymer: ethyl cellulose
•Solvent: cyclohexane

EC + Cyclohexane Polymer solution + N-
acetyl p-aminophenol (1:2)
Gelation & solidification of

coating occur
Collected by filtration, decantation &
centrifugal technique
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Addition of incompatible polymer
•Core material: Crystalline methylene blue HCl
•Coating material: Ethyl cellulose
•Solvent: Toluene
•Incompatible polymer: Polybutadiene.
EC + Toluene mixture + methylene blue HCl (1:4)

addition of Polybutadiene

EC solidify by adding non-solvent hexane,
Collected by titration & drying technique.

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Addition of Non-solvent
•Core material: Methyl scopolamine HBr
•Coating polymer: Cellulose acetate butyrate
•Solvent: Methyl ethyl ketone
•Non-solvent: Isopropyl ether.
CA butyrate + Methyl ethyl ketone mixture + methyl
scopolamine

55
0
C

mixture + isopropyl ether
(slowly cool at room temp., collected by centrifugation & drying)
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Addition of salt addition
•Core material: oil soluble vitamin
•Oil: corn oil
•Aq. phase: water
•Polymer: gelatin
•Salt: sodium sulphate
Salt : emulsion ratio is 4:10.
Oil soluble vitamin + corn oil mixture + water +
sodium sulphate
(oil droplet coated uniformly with gelation)
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polymer-polymer interaction
•Core material: Methyl salicylate
•+ve charge polymer: Gelatin
•-ve charge polymer: Gum Arabic
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Oldest industrial procedures for forming
small, coated particles or tablets.
Solid particle greater than 600 micron size Solid particle greater than 600 micron size
are generally consider for effective coating.are generally consider for effective coating.
It is used for preparation of controlled- It is used for preparation of controlled-
release beads.release beads.
Coating is applied as solution by atomized Coating is applied as solution by atomized
spray to desired solid core material in spray to desired solid core material in
coating pan.coating pan.
Usually warm air is passed over the coated Usually warm air is passed over the coated
material as the coating are being applied in material as the coating are being applied in
the coating pan.the coating pan. Oldest industrial
procedures for forming small, coated
particles or tablets.
3. Pan coating3. Pan coating
Figure Pan coaterFigure Pan coater
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Pan coatingPan coating
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4. Spray Drying and Spray Congealing
Spray Drying:
The coating solidification effected by
rapid evaporating of solvent in which
coating material is dissolved.
Spray Congealing:
The coating solidification is effected by
thermally congealing a molten coating
material. The removal of solvent is done
by sorption, extraction or evaporation
technique.
Figure Schematic diagram of a Spray Dryer
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The equipment components of a standard spray dryer include,
1.Air heater,
2.Atomizer,
3.Main spray chamber,
4.Blower or fan,
5.Cyclone and
6.Product collector.
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Spray congealing can be accomplished with spray drying equipment
when the protective coating is applied as a melt.
Core material is dispersed in a coating material melt rather than a
coating solution.
Coating solidification (and microencapsulation) is accomplished by
spraying the hot mixture into a cool air stream.
Spray congealing
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Core material
Dissolved Or Dispersed
Coating polymer solution
With Agitation
Liquid Manufacturing Vehicle Phase
Heating (If necessary)

Evaporation of Polymer solvent
Microencapsulation
5. Solvent Evaporation
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Solvent Evaporation
In the case in which the core material is dispersed in the polymer solution, polymer shrinks
around the core. In the case in which core material is dissolved in the coating polymer
solution, a matrix - type microcapsule is formed.
The core materials may be either,
water - soluble or
water - insoluble materials.
A variety of film - forming polymers can be used as coatings.
Used by companies including the NCR Company,
Gavaert Photo - Production NV, and
Fuji Photo Film Co., Ltd.
Eg. Evaluation of Sucrose Esters as Alternative Surfactants in Microencapsulation of
Proteins by the Solvent Evaporation Method.
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6. Polymerization
The method involve the reaction of monomeric unit located at the interface existing
between a core material substance and continuous phase in which the core material
is disperse.
The core material supporting phase is usually a liquid or gas, and therefore
polymerization reaction occur at liquid-liquid, liquid-gas, solid-liquid, or solid-gas
interface.
E.g. In the formation of polyamide (Nylon) polymeric reaction occurring at liquid-
liquid interface existing between aliphatic diamine & dicarboxylic acid halide.
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Types of Polymerization Technique:
Interfacial polymer: In Interfacial polymerization, the two reactants in a
polycondensation meet at an interface and react rapidly.
In-situ polymerization: In a few microencapsulation processes, the direct
polymerization of a single monomer is carried out on the particle surface. e.g. Cellulose
fibers are encapsulated in polyethylene while immersed in dry toluene. Usual
deposition rates are about 0.5μm/min. Coating thickness ranges 0.2-75μm.
Matrix polymer: In a number of processes, a core material is imbedded in a
polymeric matrix during formation of the particles. Prepares microcapsules containing
protein solutions by incorporating the protein in the aqueous diamine phase. National
Lead Corporation- utilizing polymerization techniques.
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7. Multiorifice - Centrifugal Process
SWRI develop a mechanical process that utilizes centrifugal forces to hurl, a core
material particle through an enveloping membrane.
The embryonic microcapsule, upon leaving the orifices are hardened, congealed by
variety of means.
Production rate of 50 to 75 pound/hrs have been achieved with this process.
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40. Applications of Microcapsules and Microspheres
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Agricultural Applications
Catalysis
Food Industry
Pharmaceutical Applications
Pharmaceutical Applications
Potential applications of this drug delivery system are replacement of therapeutic agents (not
taken orally today like insulin), gene therapy and in use of vaccines for treating AIDS, tumors,
cancer and diabetes.
The delivery of corrective gene sequences in the form of plasmid DNA could provide
convenient therapy for a number of genetic diseases such as cystic fibrosis and hemophilia.
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Lupin has already launched in the market worlds first Cephalexin (Ceff-ER) and Cefadroxil
(Odoxil OD) antibiotic tablets for treatment of bacterial infections.
Aspirin controlled release version ZORprin CR tablets are used for relieving arthritis
symptoms.
Quinidine gluconate CR tablets are used for treating and preventing abnormal heart rhythms.
Niaspan CR tablet is used for improving cholesterol levels and thus reducing the risk for a
heart attack.
Glucotrol (Glipizide SR) is an anti diabetic medicine used to control high blood pressure.
Some of the applications of microencapsulation can be described in detail as given
below:
1.Prolonged release dosage forms. 2. Prepare enteric-coated dosage forms selectively absorbed
in the intestine rather than the stomach. 3. It can be used to mask the taste of bitter drugs. 4.
To reduce gastric irritation. . e.g. Nitrofurantoin, Used to aid in the addition of oily medicines
to tableted dosage forms.
To overcome problems inherent in producing tablets from otherwise tacky granulations.
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This was accomplished through improved flow properties. Eg. The non-flowable
multicomponent solid mixture of niacin, riboflavin, and thiamine hydrochloride and iron
phosphate may be encapsulated and made directly into tablets.
To protect drugs from environmental hazards such as humidity, light, oxygen or heat. Eg.
vitamin A and K have been shown to be protected from moisture and oxygen through
microencapsulation.
The separations of incompatible substances, Eg. pharmaceutical eutectics.
The stability enhancement of incompatible aspirin-chlorpheniramine maleate mixture was
accomplished by microencapsulating both of them before mixing.
Microencapsulation can be used to decrease the volatility. e.g. Peppermint oil, Methyl
salicylate.
The hygroscopic properties of many core materials may be reduced by microencapsulation.
In the fabrication of multilayered tablet formulations for controlled release of medicament
contained in medial layers of tableted particles.
Microencapsulation has also been used to decrease potential danger of handling of toxic or
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Evaluation of Microencapsulation
Morphology
Drug content
Determination of % drug entrapment
Bulk density
Angle of repose
Particle size determination
In vitro dissolution studies
Diffusion Study
Floating Capabilities (only for floating – FLT & TFT)
Bioadesion/Mucoadhesion (only for GRDDS) )
In vivo Study – PK & PD (γ-Scintiography - only for GRDDS)
Stability studies.

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CHARACTERIZATION:
The characterization of the micro particulate carrier is
 important, which helps to design a suitable carrier for the
proteins, drug or antigen delivery.
These microspheres have different microstructures.
These microstructures determine the release and the stability of the carrier.
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PHYSICOCHEMICAL EVALUATION

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SIEVE ANALYSIS
Separation of the microspheres into various size
fractions can be determined by using a mechanical
sieve shaker.
A series of five standard stainless steel sieves (20,
30, 45, 60 and 80 mesh) are arranged in the order of
decreasing aperture size.
Five grams of drug loaded microspheres are placed
on the upper-most sieve.
The sieves are shaken for a period of about 10 min,
and then theparticles on the screen are weighed.
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The surface morphologies of microspheres are examined by a scanning electron
microscope.
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MORPHOLOGY OF MICROSPHERES

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A Multimode Atomic Force Microscope form Digital Instrument is used to study
the surface morphology of the microspheres.
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ATOMIC FORCE MICROSCOPY (AFM)

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Particle size determination:
Approximately 30 mg microparticles is redisposed in 2–3 ml distilled water, containing 0.1%
(m/m) Tween 20 for 3 min, using ultrasound. Then transferred into the small volume
recirculating unit, operating at 60 ml/ s.
The microparticles size can be determined by laser diffractometry.
laser diffracto meter
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PARTICLE SIZE

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POLYMER SOLUBILITY IN THE
SOLVENTS
Solution turbidity is a strong indication of solvent power .
The cloud point can be used for the determination of the solubility of the polymer in
different organic solvents.
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The absolute viscosity, kinematic
viscosity, and the intrinsic
viscosity of the polymer solutions
in different solvents can be
measured by a U-tube viscometer.
The polymer solutions are allowed
to stand for 24 h prior to
measurement to ensure complète
polymère dissolution.
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VISCOSITY OF THE POLYMER SOLUTIONS

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DENSITY DETERMINATION
The density of the microspheres can be measured
by using a multi volume pychnometer.
Accurately weighed sample in a cup is placed into
the multi volume pychnometer.
Helium is introduced at a constant pressure in the
chamber and allowed to expand. This expansion
results in a decrease in pressure within the chamber.
Two consecutive readings of reduction in pressure
at different initial pressure are noted.
From two pressure readings the volume and
density of the microsphere carrier is determined.
Multi volume pychnometer
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BULK DENSITY
The microspheres fabricated are weighed and
transferred to a 10-ml glass graduated cylinder.
The cylinder is tapped until the microsphere
bed volume is stabilized.
The bulk density is estimated by the ratio of
microsphere weight to the final volume of the
tapped microsphere bed.
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CAPTURE EFFICIENCY
The capture efficiency of the microspheres or the percent entrapment can be
determined.
The sample is then subjected to the determination of active constituents as per
monograph requirement.
The percent encapsulation efficiency is calculated using equation:
% Entrapment: Actual content/Theoretical content x 100
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ANGLE OF CONTACT
The angle of contact is measured to determine the wetting property of a micro
particulate carrier.
To determine the nature of microspheres in terms of hydrophilicity or
hydrophobicity.
This thermodynamic property is specific to solid and affected by the presence of the
adsorbed component.
The angle of contact is measured at the solid/air/water interface.
The advancing and receding angle of contact are measured by placing a droplet in a
circular cell mounted above objective of inverted microscope.
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IN VITRO METHODS
There is a need for experimental methods which allow the release characteristics and
permeability of a drug through membrane to be determined.
For this purpose, a number of in vitro and in vivo techniques have been reported.
In vitro drug release studies are employed as a quality control procedure in pharmaceutical
production, in product development etc.
The influence of technologically defined conditions and difficulty in simulating in vivo
conditions has led to development of a number of in vitro release methods for buccal
formulations; however no standard in vitro method has yet been developed.
Different workers have used apparatus of varying designs and under varying conditions,
depending on the shape and application of the dosage form developed.
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BEAKER METHOD
The dosage form in this method is made to adhere at the bottom of the beaker
containing the medium and stirred uniformly using over head stirrer.
Volume of the medium used in the literature for the
-studies varies from 50- 500 ml
-stirrer speed form 60-300 rpm.
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Standard USP or BP dissolution apparatus have been used to study in vitro release
profiles.
Dissolution medium used for the study varied from 100-500 ml and speed of
rotation from 50-100 rpm.
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DISSOLUTION APPARATUS

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Factors Influencing Encapsulation Efficiency
The encapsulation efficiency of the microparticles or microcapsule or microsphere will be affected by different
parameters, Fig.5 illustrate the factors influencing encapsulation efficiency.
Figure 5: Factors influencing encapsulation efficiency

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Solubility of polymer in the organic solvent
Mehta et al., 1996
31
, studied the effect of solubilities of the polymers of different PLGAs in methylene chloride were
compared by measuring the methanol cloud point (Cs): Higher Cs meant that the polymer was more soluble in methylene
chloride and, thus, required a greater amount of methanol to precipitate from the polymer solution. The PLGA polymer of a
relatively high L/G ratio (75/25) had a higher solubility in methylene chloride than the other PLGA (L/G ratio=50/50). A
lower molecular weight polymer had a higher solubility in methylene chloride than a higher molecular weight polymer. End-
capped polymers, which were more hydrophobic than non-end-capped polymers of the same molecular weight and
component ratio, were more soluble in methylene chloride.
Diffusion of drugs into the continuous phase mostly occurred during the first 10 minutes of emulsification; therefore, as the
time the polymer phase stayed in the non-solidified (semi-solid) state was extended, encapsulation efficiency became
relatively low. In Mehta’s study, polymers having relatively high solubilities in methylene chloride took longer to solidify
and resulted in low encapsulation efficiencies, and vice versa
31
. Particle size and bulk density also varied according to the
polymer. Since polymers having higher solubilities in methylene chloride stayed longer in the semi-solid state, the dispersed
phase became more concentrated before it completely solidified, resulting in denser microparticles.
Johansen et al., 1998
32
shown that the use of relatively hydrophilic PLGA which carried free carboxylic end groups resulted
in a significantly higher encapsulation efficiency compared to that of an end-capped polymer. A similar explanation as above
applies to this observation: Hydrophilic PLGA is relatively less soluble in the solvent, methylene chloride, and precipitates
more quickly than the end-capped one. High solidification rate might have increased the encapsulation efficiency. On the
other hand, the authors attribute the increase to the enhanced interaction between PLGA and the protein through hydrogen
bonding and polar interactions
32
. Walter et al
33
. also observed an increased encapsulation efficiency from using relatively
hydrophilic PLGA in DNA microencapsulation. The hydrophilicity of the polymer enhanced the stability of the primary
emulsion, and it contributed to such an increase.

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Solubility of organic solvent in water
Bodmeier et al
34
. found that methylene chloride resulted in a higher encapsulation efficiency as compared with chloroform
or benzene, even though methylene chloride was a better solvent for poly (lactic acid) (PLA) than the others. Methylene
chloride is more soluble in water than chloroform or benzene. The ‘high’ solubility allowed relatively fast mass-transfer
between the dispersed and the continuous phases and led to fast precipitation of the polymer. The significance of solubility
of the organic solvent in water was also confirmed by the fact that the addition of water-miscible co-solvents such as
acetone, methanol, ethyl acetate, or dimethyl sulfoxide (DMSO), contributed to increase of the encapsulation efficiency.
Knowing that the methanol is a non-solvent for PLA and a water-miscible solvent, it can be assumed that methanol played a
dual function in facilitating the polymer precipitation: First, the presence of methanol in the dispersed phase decreased the
polymer solubility in the dispersed phase (Jeyanthi et al., 1997)
35
. Second, as a water-miscible solvent, methanol facilitated
diffusion of water into the dispersed phase.
In order to explain the low encapsulation efficiency obtained with benzene, the authors mention that the benzene required a
larger amount of water (non-solvent) than methylene chloride for precipitation of the polymer, and the drug was lost due to
the delayed solidification. However, given that benzene is a poorer solvent than methylene chloride for a PLA polymer, this
argument does not agree with the widely spread idea that a poor solvent requires a smaller amount of non-solvent to
precipitate a polymer. In fact, there could have been a better explanation if they had considered that the delayed
solidification was due to the low solubility of benzene in water: As a poor solvent for a PLA polymer, benzene requires
only a small amount of non-solvent for complete solidification of the polymer. However, since benzene can dissolve only a
tiny fraction of water, it takes much longer to uptake water into the dispersed phase. That is, while solubility of a polymer
in an organic solvent governs the quantity of a nonsolvent required in precipitating a polymer, solubility of the organic
solvent in the non-solvent limits diffusion of the non-solvent into the polymer phase. Thus, when a cosolvent system is
involved, both solubility of a polymer in a solvent and solubility of the solvent in a non-solvent participate in determining
the solidification rate of the dispersed phase.

61. 04/06/16 sagar kishor savale 61
Park et al., 1998
36
, lysozyme-loaded PLGA microparticles were prepared using the oil in water (o/w) single emulsion
technique. Here, the authors used a co-solvent system, varying the ratio of the component solvents. DMSO was used for
solubilization of lysozyme and PLGA, and methylene chloride was used for generation of emulsion drops as well as
solubilization of PLGA. Encapsulation efficiency increased, and initial burst decreased as the volume fraction of DMSO in
the co-solvent system increased. Particle size increased, and density of the microparticle matrix decreased with increasing
DMSO. Overall, these results indicate that the presence of DMSO increased the hydrophilicity of the solvent system and
allowed fast extraction of the solvent into the continuous phase, which led to higher encapsulation efficiency and larger
particle size.
Concentration of the polymer
Encapsulation efficiency increases with increasing polymer concentration (Mehta et al., 1996; Rafati et al., 1997; Li et al.,
1999)
31, 37, 38
. For example, the encapsulation efficiency increased from 53.1 to 70.9% when concentration of the polymer
increased from 20.0 to 32.5% (Mehta et al., 1996)
31
. High viscosity and fast solidification of the dispersed phase contributed
to reducing porosity of the microparticles as well (Schlicher et al., 1997)
39
. The contribution of a high polymer concentration
to the encapsulation efficiency can be interpreted in two ways. First, when highly concentrated, the polymer precipitates
faster on the surface of the dispersed phase and prevents drug diffusion across the phase boundary (Rafati et al., 1997)
37
.
Second, the high concentration increases viscosity of the solution and delays the drug diffusion within the polymer droplets
(Bodmeier and McGinity, 1988)
34
.

62. 04/06/16 sagar kishor savale 62
Ratio of dispersed phase to continuous phase (DP/ CP
ratio)
Encapsulation efficiency and particle size increase as the volume of the continuous phase increases (Li et al., 1999, Mehta et
al., 1996)
38,31
. For example, the encapsulation efficiency increased more than twice as the ratio of the dispersed phase to the
continuous phase (DP/CP ratio) decreased from 1/50 to 1/300 (Mehta et al., 1996)
31
. It is likely that a large volume of
continuous phase provides a high concentration gradient of the organic solvent across the phase boundary by diluting the
solvent, leading to fast solidification of the microparticles. A relevant observation is described in the literature (Sah, 1997)
40
.
In this example, which utilized ethyl acetate as a solvent, the formation of microparticles was dependent on the volume of
the continuous phase. When 8 mL of PLGA solution (o) was poured into 20 or 50 mL of water phase (w), the polymer
solution was well disintegrated into dispersed droplets. On the other hand, when the continuous phase was 80 mL or more,
the microspheres hardened quickly and formed irregular precipitates. This is because the large volume of continuous phase
provided nearly a sink condition for ethyl acetate and extracted the solvent instantly. Due to the fast solidification of the
polymer, particle size increased with increasing volume of the continuous phase. Microparticles generated from a low
DP/CP ratio had a lower bulk density (0.561 g/cc at 1/50 vs. 0.357 g/cc at 1/ 300), which the authors interpret as an
indication of higher porosity of the polymer matrix (Mehta et al., 1996)
31
. On the other hand, a different example shows that
a higher DP/ CP ratio resulted in increased porosity, providing a large specific surface area (measured by the BET method)
and the scanning electron microscope (SEM) pictures as evidence (Jeyanthi et al., 1997)
35
. This apparent discrepancy can be
explained by the fact that low bulk density (Mehta et al., 1996)
31
is not a true reflection of porosity but a result of large
particle size. In fact, porosity increases with increasing DP/CP ratio, i.e., decreasing rate of the polymer precipitation.

63. 04/06/16 sagar kishor savale 63
Rate of solvent removal
The method and rate of solvent removal influence the solidification rate of the dispersed phase as well as morphology of
the resulting microparticles (Mehta et al., 1994)
41
. In the emulsion-solvent evaporation/extraction method, the solvent can
be removed by (i) evaporation, in which the solvent is evaporated around its boiling point or (ii) extraction into the
continuous phase. The rate of solvent removal can be controlled by the temperature ramp or the evaporation temperature in
the former and by the volume of the dilution medium in the latter. PLGA microparticles containing salmon calcitonin
(sCT) were prepared by emulsification, followed by different solvent removal processes (Mehta et al., 1994, Jeyanthi et
al., 1996)
41,42
. In the temperature dependent solvent removal process, the solvent (methylene chloride) was removed by
increasing the temperature from 15 to 40°C at different rates. The microparticles that resulted from this process had a
hollow core and a porous wall. The core size and wall thickness were dependent on the temperature ramp. A rapid rise in
temperature resulted in a thin wall and a large hollow core, whereas a stepwise temperature rise (15 to 25, then to 40°C)
resulted in a reduced core size. It is believed that the hollow core was due to the rapid expansion of methylene chloride
entrapped within the solidified microparticles. In controlled extraction of the solvent, the solvent was removed gradually
and slowly by dilution of the continuous phase, which left the microparticles in the soft state for a longer period of time.
The resulting microparticles showed a highly porous honeycomb- like internal structure without a hollow core. In the later
study, it was noted that the porosity was a function of the amount of water diffused into the dispersed phase from the
continuous phase, which could only be allowed before the dispersed phase solidified completely (Li et al., 1995)
43
. In
other words, the high porosity of the microparticles was due to the slow solidification of the microparticles. Even though it
is generally assumed that fast polymer solidification results in high encapsulation efficiency, this does not apply to the
observation of Yang et al.
44
. Here, the encapsulation efficiency was not affected by the solvent evaporation temperature. It
may be due to the different processing temperatures influenced not only the rate of polymer solidification but also the
diffusivity of the protein and its solubility in water. While the high temperature facilitated solidification of the dispersed
phase, it enhanced diffusion of the protein into the continuous phase, compromising the positive effect from the fast
solidification.

64. 04/06/16 sagar kishor savale 64
Interaction between drug and polymer
Interaction between protein and polymer contributes to increasing encapsulation efficiency
45
. Generally, proteins are
capable of ionic interactions and are better encapsulated within polymers that carry free carboxylic end groups than the end-
capped polymers. On the other hand, if hydrophobic interaction is a dominant force between the protein and the polymer,
relatively hydrophobic end-capped polymers are more advantageous in increasing encapsulation efficiency
31
. For example,
encapsulation efficiencies of more than 60% were achieved for salmon calcitonin (sCT) microparticles despite the high
solubility of sCT in the continuous phase
35
. This is attributed to the strong affinity of sCT to hydrophobic polymers such as
PLGA. On the other hand, such interactions between protein and polymer can limit protein release from the
microparticles
36,46,47
. In certain cases, a co-encapsulated excipient can mediate the interaction between protein and polymer
32
.
Encapsulation efficiency increased when gammahydroxypropylcyclodextrin (g-HPCD) were co-encapsulated with tetanus
toxoid in PLGA microparticles. It is supposed that the g-HPCD increased the interaction by accommodating amino acid side
groups of the toxoid into its cavity and simultaneously interacting with PLGA through van der Waals and hydrogen bonding
forces.
Solubility of drug in continuous phase
Drug loss into the continuous phase occurs while the dispersed phase stays in a transitional, semi-solid state.
If the solubility of the drug in the continuous phase is higher than in the dispersed phase, the drug will easily
diffuse into the continuous phase during this stage. For example, the encapsulation efficiency of quinidine
sulfate was 40 times higher in the alkaline continuous phase (pH 12, in which quinidine sulfate is insoluble)
than in the neutral continuous phase (pH 7, in which quinidine sulfate is very soluble)
34
.

65. 04/06/16 sagar kishor savale 65
Molecular weight of the polymer
X. Fu et al., studied the effect of molecular weight of the polymer on encapsulation efficiency, developed a long-acting
injectable huperzine A-PLGA microsphere for the chronic therapy of Alzheimer's disease, the microsphere was prepared by
using o/w emulsion solvent extraction evaporation method. The morphology of the microspheres was observed by scanning
electron microscopy. The distribution of the drug within microspheres was observed by a confocal laser scanning
microscope. The results indicated that the PLGA 15 000 microspheres possessed a smooth and round appearance with
average particle size of 50 µm or so. The encapsulation percentages of microspheres prepared from PLGA 15 000, 20 000
and 30 000 were 62.75, 27.52 and 16.63%, respectively. The drug release percentage during the first day decreased from
22.52% of PLGA 30 000 microspheres to 3.97% of PLGA 15 000 microspheres, the complete release could be prolonged to
3 weeks. The initial burst release of microspheres with higher molecular weight PLGA could be explained by the
inhomogeneous distribution of drug within microspheres. The encapsulation efficiency of the microspheres improved as the
polymer concentration increase in oil phase and PVA concentration decreased in aqueous phase. The burst release could be
controlled by reducing the polymer concentration. Evaporation temperature had a large effect on the drug release profiles. It
had better be controlled under 30°C. Within a certain range of particle size, encapsulation efficiency decreased and drug
release rate increased with the reducing of the particle size
48
.
Summery of Factors of Encapsulation Efficiency
The techniques reviewed in this article would serve as a forerunner for developing novel drug delivery towards ensuring
better therapeutic efficiency. The factors influencing their optimisation provides a clear picture towards developing a
suitable technique not only for drug industry but also for other food and cosmetic industry as well. Care full consideration of
the above said factors would ensures reproducibility in both lab and production scale.

66. 6666
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