Methods of microencapsulation

AISSMS college of Pharmacy, Pune

Introduction:
• As a process, microencapsulation is means of applying the
thin coating to small particles of solids or droplets of liquids
and dispersions.
• Microcapsule often described by terms such as microspheres,
coated granules, microsperules, spansules, etc.
• The first microencapsulation procedure was published by
Bungenburg de Jong and Kaas1 in 1931 which deals with
preparation of gelatin microspheres by Coacervation process.
• In late 1930s & 1940s, Green et. al. of National Cash register
Co., Dayton, Ohio, developed gelatin coacervation process
which eventually leads to several patents for carbonless
carbon paper manufacturing by use of gelatin coacervation
made microencapsulation process more common.
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Dimensions:
• At present, there is no universally accepted size range that
particles must have in order to be classified as microcapsules.
• However, many workers classify capsules as follows
(according to the Simon Benita2):
Diameter Type of capsule
Less than 1 micron Nanocapsule
3 to 800 micron Microcapsule
Larger than 1000 micron Macrocapsule

• Bakan3 described capsules dimensionally ranging from 10 to

5000 micron as microcapsules.

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Application of microencapsulation:
• Conversion of liquids to solid
• Alteration of colloidal and surface properties
• Protection from environmental condition
• Prolonged action or sustained release formulation
• Targeted release formulation
• Taste and odor masking
• Formulation of medicament with reduced gastric irritation
properties
• Single layered tablet containing chemically incompatible
ingredients
• New formulation concept for creams, ointments, aerosols, etc

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Demerits of microencapsulation:
• No single microencapsulation process is adaptable to all core
material candidate or product applications
• Complicated process and requires skilled labor to supervise
• Incomplete or discontinuous coating
• Nonreproducible & unstable release characteristics of coated
products
• Inadequate stability or shelf-life of sensitive pharmaceuticals
• Economic limitations

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Core material:
• It is the specific material to be coated and it also referred as
nucleus or fill
• It can be solid or liquid in nature
• Examples of some core material as follows:

Core Material Characteristic Purpose of Final Product Form

Property Encapsulation
Acetaminophen Solid Taste masking Tablet
Aspirin Solid Taste masking; Tablet or capsule
sustained release;
reduced gastric
irritation

Vitamin A Nonvolatile liquid Stabilization to Dry powder

palmitate oxidation 6
Core Material Characteristic Purpose of Final Product Form
Property Encapsulation
Urease Water soluble Permeseletivity of Dispersion
enzyme enzyme , substrate
and reaction
product
Progesterone Slightly water Sustained release Varied
soluble solid
Islets of Langerhans Viable cells Sustained Injectable
normalization of
diabetic condition
Isosorbide dinitrate Water-soluble solid Sustained release Capsule
Potassium chloride Highly water soluble Reduced gastric Capsule
solid irritation
Activated charcoal Adsorbent Selective sorption Dry powder
Liquid crystals Liquid Conversion of liquid Flexible film for
to solid thermal mapping of
anatomy
Castor oil Liquid Conversion to solid Varied
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Coating materials:
• These are the material used for coating the core material and
these are also referred as wall or shell.
• Depending upon the method of microencapsulation employed
& properties of final product needed, coatings solution may
contain different additive such as film formers, plasticizers, and
fillers and may be applied through different solvent system.
• Examples as follows:

Film formers:
Poly acrylamides, Polyacryldextrans, Polyalkyl cyanoacrylate, Agar, Agarose,
Alginates, Cellulose derivatives, Cetyl alchol, Gelatin, Gluten, Polyester, Polyamide,
Starch, Shellac, Stearic acid, Polyvinyl alchol, Waxes, etc.

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Solvents:
Water, Methanol, Ethanol, n-Propanol, Acetone, Ethyl acetate, Choloroform, etc.

Plasticizers:
Castor oil, Glycols, Glycerin, Polysorbates, Phthalate esters, Fatty acid esters, etc.
Surfactants:
Carboxylic acid, Alkyl sulphonates, Alkoxyalkylamines, etc

Crosslinking agents:
Formaldehyde , Glutaraldehydes, etc
Antitack agents:
Fatty acids such as Stearic acid, Palmitic acid, etc
Colorant:
Various insoluble lakes
Fillers:
Talc and other silicates

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 Methods of microencapsulation:
1. Coacervation-phase separation
2. Pan coating
3. Air suspension
4. Spray drying & Spray congealing
5. Spray embedding & Spray polycondensation
6. In situ polymerization
7. Interfacial polymerization in liquid media
8. Multiorifice centrifugal extrusion
9. Solvent evaporation
10. Microencapsulation using ultrasonic atomizer
11. Dip coating
12. Electrostatic encapsulation
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Coacervation-phase separation:
• The term coacervation is derived from the Latin acervus,
meaning aggregation, and the prefix co to indicate union of
colloidal particles. Bungenburg de Jong and Kruyt5 described
this term in 1929.
• This process is attributed to the National Cash Register Co.
(NCR), Dayton, Ohio & the patents of B. K. Green et al6-9.
• The general outline of the process consists of three steps
carried out under continuous agitation:
1. Formation of three immiscible chemical phases
2. Deposition of the coating
3. Rigidization of the coating

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Formation of three immiscible chemical phases:

• Three immiscible chemical phases are liquid manufacturing

vehicle phase, core material phase & coating material phase.
• The coating material phase, an immiscible polymer in a liquid
state, is formed by utilizing one the methods of phase
separation-coacervation:
1. By changing the temperature of the polymer solution
2. By adding a salt to the polymer solution
3. By adding a nonsolvent to the polymer solution
4. By adding incompatible polymer to the polymer solution
5. By inducing a polymer-polymer interaction

12
Deposition of the coating:
• This step consists of depositing the liquid polymer coating
upon the core material.
• Deposition of the liquid polymer coating around the core
material occurs if the polymer adsorbed at the interface
formed between the core material and liquid vehicle phase,
and this adsorption phenomenon is a prerequisite to effective
coating.
• The continued deposition of the coating material is promoted
by a reduction in total free interfacial energy of the system

Rigidization of coating:
• It is carried out usually by thermal cross-linking or desolvation
technique, to form self sustaining microcapsules
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Pan coating:
• Most widely used method but much literature publication is
concerned with industrial patents, whereas the finer details
procedure are inadequately described.
• Unlike many other microencapsulation processes, the process
tends itself to great flexibility in formulation of coating.
• Also core material may contain wide range of additive may
serve to modify release properties of formulation.
• Pan coating method of microencapsulation process contains
two steps:
1. Preparation of core material
2. Coating procedure

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 Preparation of core material:
• For the satisfactory pan coating core particles should be of
greater than 500 micron, spherical shape, adequate hardness
and low friability.
• Very few drugs satisfy these requirement hence the following
approaches are used for preparation of core:
1.Use of spherical substrate such as nonpareil sugar seeds
( described by Enz & King in patent assigned to Upjohn Co 11.)
2.Coating of fine powdered medicament to the large crystal of
same medicament ( described by Heimlich & MacDonnell in
patent assigned to Smith, Kline and French laboratories 12)
3. Incorporation drug into suitable matrix material (described by
Brophy and Deasy.13)
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Coating procedure:
• Steps involved in coating of batch of cores:
1. Roughening of inner surface of pan if it not contain
baffle
2. Screening of core material to remove dust
3. Core material addition
a. Pour method
b. Spray method
4. Addition of dusting powder such as talc at the critical
moment just as core become tacky and just in sufficient amount
to free up any clumps
5. Drying and jogging after each application of coating
6. 20-50 application of coating & drying in flat trays at 400C
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Equipment and related facilities:
Pan coating apparatus

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Applications of pan coating:
• Lowy14 pan coated rounded granules containing nitroglycerine
with various cellulose derivatives such as methylcellulose,
ethylcellulose, or cellulose acetate using beeswax or castor oil
as a plasticizer.
• Rosen and Swintoskey15 reported pan coating of trimeperazine
that contain following step:
1. 35S-labeled trimeperazine tartarte, an antipuritic agent,
mixed with powdered starch and sugar
2. This is applied on sugar pellet using hydroalcholic gelatin
adhesive in coating pan
3. Dried, screened and then coated with solution of 11%
w/w glyceryl monostearate, 11% w/w glyceryl monostearate &
3% w/w white beeswax in CCl4, resulted microcapsules showed
sustained release in human subjects after oral administration.
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Air suspension technique:
• Air suspension coat was originally developed by Wurster et. al.,
is an attractive alternative to pan coating
• Process & application described by Wurster in series of patents
assigned to Wisconsin Alumni Research Foundation 16-22
• It has following advantages over pan coating:
1. More rapid
2. No need of skilled labor, often fully automated
3. Coat continuity is superior & less coating solution
required
4. No loss of coating material as being closed system

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Equipment:

20
Process consideration:
• Air distribution & Flow rate
• Atomizer type & feed
• Solvent selection
• Solvent evaporation
• Temperature profile
• Core size & shape
• Particle interaction

Coating chamber of wurster

process

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Application of air suspension:
• Coletta & Rubin23 described coating of aspirin crystals of
various mesh sizes with mixtures of ethyl cellulose & methyl
cellulose sprayed from methylene chloride : isopropyl alcohol
(1:1) solution using Wurster air suspension apparatus.
• Caldwell & Rosen24 used an air suspension coater to
successfully apply dexamphetamine sulphate onto sugar
pellets using solution of gelatin in hydroalcholic solvent as
adhesive. Then coated with various materials, including
beeswax, glyceryl monostearate and distearate to obtain lipid
coated microcapsules with sustained release properties.

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Spray drying and spray congealing:
• In spray drying process the core substance is dispersed in a
solution of coating material, which is then atomized and the
dried off using heated air.
• Spray congealing, the substance which has property of
melting at elevated temperature when being atomized and
congealing when the droplet formed meet cool air on spray
dryer.
Advantages:
• Rapid, single stage operation, can be used for heat sensitive
substance
Disadvantages:
• Porous coating, not suitable for taste & odor masking and for
controlled release formulation, high cost of production
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Equipment & process:
• Arrangement of equipment for both process is same.

Schematic diagram for concurrent spray dryer

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Applications of spray drying:
• Marotta et al.25, in patent assigned to National Starch and
Chemical Corporation, used an aqueous solution of acid ester
dextrins to encapsulate emulsified dispersion lemon oil by
spray drying.
• Sager26, in patent assigned to Beecham Group ltd., Great
Britain, described spray drying of penicillin as follows:
1. As an example of process, high concentrated ampicillin
trihydrate suspended in dilute solution of sodium
carboxymethylcellulose.
2. Control of foaming by addition of ethanol
3. Filtration
4. Spray dried at 1600C and outlet temperature is 840C
5. Product less than 75 micron are recycled
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Applications of spray congealing:
• Robinson and Swintosky27 microencapsulated particles of
sulfaethylthiadiazole by mixing them with molten
hydrogenated castor oil at 1100C; then suspension was spray
congealed into air cooled chamber using centrifugal wheel
atomizer.
• Koff28 dispersed thiamine monohydrate into a molten mixture
of mono- and diglycerides of palmitic and stearic acid at 740C
and spray congealed into ambient air at 200C. Average
particle size is about 60 micron and the process was reported
to be suitable for the encapsulation of vitamin of B group for
taste masking purpose.

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Spray embedding & spray polycondensation:

Spray embedding:
• In this aqueous or organic solvent containing solution of both
drug and dissolution retarding polymer are spray dried.
• Takenaka et al29. spray dried ammoniacal solution of
sulfamethoxazole and cellulose acetate phthalate.
Spray polycondensation:
• This process is based on spray drying whereby a dispersion of
core material in continuous phase containing reactive
monomer and precondensate with catalyst, in addition to
other film forming agent, is caused polymerize at high
temperature of the process by solvent evaporation
• Voemelly et al30. used this process to microencapsulate
phenobarbital
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In-situ polymerization:
• It is also known as normal polymerization.
• By this technique, one can produce capsules and particles in
micrometer and nanometer range.
• Polymerization techniques of pharmaceutical interest is
carried out in liquid phase and they have following types
1. Bulk polymerization
2. Suspension polymerization
3. Emulsion polymerization
4. Micelle polymerization

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Bulk polymerization:
• In this, mixture of monomer and drug are heated.
• Initiator added to accelerate the rate of the reaction.
• During polymerization viscosity is maintained by temperature.
• The polymer so obtained may be molded or fragmented as
microsphere.
Advantage:
• Relatively pure polymers are formed.
Disadvantages:
• Difficult to dissipate high exothermic heat of reaction
• Polymer blocks are formed which need mechanical
fragmentation causing irregular size, shape & release

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Suspension polymerization:
• Referred as bead polymerization or pearl polymerization
• It involves heating of water insoluble monomer and drug as
dispersion droplet
• Drug droplet contain initiator
• Aqueous phase may also contain stabilizers, fillers, buffers,
electrolytes, etc.
• Washing after completion of process
Advantages:
• Heat of polymerization is absorbed by continuous phase
• Spherical beads are of uniform size and release characteristics
Disadvantages:
• Difficulty from freeing the product from unwanted additives
• Coalescence problem
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Emulsion polymerization:
• Differs from suspension polymerization by three ways : Initiator
in aqueous phase , More vigorous agitation, Surfactant present in
much higher concentration
• This results in altered mechanisms of polymerization:
1. Excess surfactant forms micelles and take up part of
monomer cause them to swell
2. Initiator generated radical (by heat or irradiation) start
polymerization
3. As monomer consumed replaced by replaced by remaining
monomer by passive diffusion
Advantages:
• Higher molecular weight polymer formed at faster rate
Disadvantages:
• Unreacted monomer which are in higher concentration
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Micelle polymerization:
• Differs from emulsion polymerization in that all of monomer and
drug is present in micelle produced by surfactant present in
suitable concentration.
• Diffusion of monomer is prevent by nonsolvent properties of
outer phase used.
• Hence no product swelling occur.
Advantages:
• Capsules dimensionally ranging from few nanometers can be
formulated.
Disadvantages:
• Difficulties in product recovery due to minute size

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Application of in-situ polymerization:
• Nilsson et al.31 used suspension polymerization technique to
immobilize trypsin.
Steps involved:
• Enzyme dissolved with acrylamide (monomer) and N,N’-bis-
acrylamide (crosslinking agent) in aqueous triethanolamine-
HCl at buffer pH 7.
• Addition of ammonium persulfate (radical initiator) and
N,N,N’,N’,-tetramethylethylenediamine (accelerator) in
aqueous phase
• Aqueous phase added to organic phase (toluene : chloroform
290 : 110) to form w/o dispersion.
• Polymerization carried out at 40C under nitrogen for 30 min
• Filtration and washing with toluene
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Interfacial polymerization:
• It involves reaction of various monomers at the interface
between two immiscible liquid phases
Steps involved:
• One reactive polymer dissolved in aqueous disperse phase
containing a solution or dispersion of the core material.
• Other reactive monomer dissolved after emulsification in
nonaqueous continuous phase
• Monomer diffuse together and rapidly polymerizes at
interface
• Byproducts of reaction is neutralized by added product such
as alkaline buffer
Advantages:
• Rapid, Products are relatively uniform in size
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Interfacial polymerization:

Disadvantages:
• Toxicity problem associated with unreacted monomer
• Excessive drug degradation caused by reaction with monomer
• Fragility of formed product
• Lack of biodegradability of product
Application:
• Chang32-33 published his work of nylon microencapsulation for
immobilization of various enzymes

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Multiorifice centrifugal process:
• This mechanical process for production of microcapsules is
produced by Southwest Research Institute (SwRI).
schematic diagram of multiorifice-centrifugal microencapsulation apparatus

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Applications of multiorifice-centrifugal process:

• Somerville et al.34, in work financially supported by Beecham

Laboratories, reported use of the SwRI multiorifice centrifugal
extrusion process for the microencapsulation of quinidine
sulfate.
• Mangold et al.35 also reported preliminary results using the
SwRI centrifugal extrusion device for the microencapsulation
of ethynylestradiol, norethindrone, and norethindrone
acetate in mixtures of various glycerides and fatty acids or
alcohols in order to reduce undesirable side effects
associated with the daily peaks produced by conventional
orally administered contraceptive therapy.

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Solvent evaporation:
• This technique is based on the evaporation of the internal
phase of an emulsion by agitation.
• This technique has been used by companies including The
NCR company, Gavaert Photo Production NV and Fuji Photo
Film Co., Ltd.36-39 to produce microcapsules.
• It is applicable to a wide variety of liquid or solid core
material.
• This technique has following types:
1. Single emulsion evaporation
2. Multiple emulsion evaporation

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Single emulsion evaporation:
o/w emulsion evaporation:
• Steps involved are as follows (described by Morishita et al in
patent assigned to Toyo Jozo Co. Ltd., Japan40):
1. Drug is dissolved or dispersed in a solution of polymer in
single or mixed organic solvent having low boiling point
2. Emulsified into aqueous phase and stabilized by surfactant
to o/w emulsion
3. Evaporation of solvent by reduced pressure and/or heat
4. Collection of microspheres by filtration or centrifugation
• Mortada41 dispersed sulfathiazole in solution of ethylcellulose
in trichloromethane.
Surfactant used: 0.04% sodium lauryl sulphate
Solvent evaporation by stirring for 5hrs at room temperature
39
Multiple emulsion evaporation:
w/o /w emulsion evaporation:
• Steps involved are as follows (described in series of patent
assigned to Gaevert Photo Production NV42-44):
1. aqueous solution or dispersions of drugs is emulsified into
hydrophobic polymer dissolved in water immiscible solvent
having a boiling point below 1000C
2. Initially formed w/o emulsion is emulsified into an aqueous
solution of hydrophilic colloid
3. By raising temperature the organic solvent is evaporated
causing phase separation of the polymer as coating around
the inner aqueous droplet
4. Alternatively, addition of organic solvent which is
immiscible with solvent and miscible with core & coating
material, removes organic solvent
40
• It is used to produce microencapsules with distinct walls.
• This approach has been used to produce polystyrene
microencapsules containing placental alkaline phosphatase by
Takenaka et al.45 and α-amylase or sodium salicylate by
Nowaza and Higashida.46

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Dip coating:
• This process involves single or repeated dipping cores into a
coating solutions.
• Because of the static nature of the process, major difficulty is
damage to the coating.
• Gagnon et al.47 dip coated the aspirin containing granules
with stearic acid.
• Andrade et al.48 dip coated activated carbon granules by
placing them in mesh sack and immersing them into alcoholic
solution of hydroxyethyl methacrylate (HEMA) containg butyl
peroctoate as initiator.

42
Electrostatic encapsulation:
Electrostatic encapsulation chamber
• This method is developed at
Illinois Institute of Research
and technology, Chicago.
• Langer & Yamate49 successfully
encapsulated glycerin with
carnauba wax using this
process. The microcapsules
formed are of smaller than 5
micron.
• Larger particles are not
possible as it requires high
voltage & also they lack
Brownian motion.
43
Microencapsulation using ultrasonic atomizer:

• Yoon Yeo & Kinam Park 50reported this method in 2004.

Schematic representation of the microencapsulation system

using coaxial ultrasonic atomizer

44
Mechanism and applications:
• With the aid of confocal laser scanning microscopy,
fluorescence microscopy, drug release study; they found
mechanism of formation of microcapsule as follows:
1. It is based on midair collision among multiple drops of
components of liquids and subsequent mass transfer at their
interface.
2. The microcapsule formed as the result of collision
between fluid drops, hence core material not subjected to
strong mechanical stress & only briefly exposed to mild
ultrasonic vibrations less than few watt, which is far below
the damaging level.
• Protein was mainly taken into consideration while designing
this method of microencapsulation.
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References:
1. H. G. Bungenburg de Jong & A. J. Kaas , Zar Kennetus komplex –
koazeration, V. Mitteilung: relative verschiebumer im
elektrischen gleichstromfeide von fllussigkeits-einschliebungen
in komplex-kooazervat-tropfehen, Biochem. Z.,232:338-345
(1931).
2. S. Benita, Microencapsulation: Methods and Industrial
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p.p. 358-360 (2008).

46
5. H. G. Bungenberg de Jong & H. R. Kruyt, Chemistry-
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6. B. K. Green: U.S. Patent: 2,712,507 (1955).
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8. B. K. Green: U.S. Patent: 2,800,457 (1957).B. K. Green: U.S.
Patent Re: 24,899 (1960).
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48
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49
32. T. M. S. Chang, Semipermeable Microcapsules, Science 146 :
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50
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51
46. Y.Nozawa . Drug release from and properties of
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(2004).

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Questions...
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