Microencapsulation – A Novel Approach in Drug Delivery: A Review

Abstract

The review of Microencapsulation is a well-established dedicated to the preparation, properties and uses of individually encapsulated novel small particles, as well as significant improvements to tried-and-tested techniques relevant to micro and nano particles and their use in a wide variety of industrial, engineering, pharmaceutical, biotechnology and research applications. Its scope extends beyond conventional microcapsules to all other small particulate systems such as self-assembling structures that involve preparative manipulation. The review covers encapsulation materials, physics of release through the capsule wall and / or desorption from carrier, techniques of preparation, many uses to which microcapsules are put.© 2011 IGJPS. All rights reserved.

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Microencapsulation – A Novel Approach in Drug Delivery: A Review
Nitika Agnihotri, Ravinesh Mishra*, Chirag Goda, Manu Arora
Institute of Pharmacy & Emerging Sciences, Baddi University of Emerging Sciences & Technology, Makhnumajra, Baddi, Distt. Solan, H.P-173205,
India
Address for Correspondance: ravi_kcp@rediffmail.com ; chirag.goda@gmail.com
ABSTRACT: The review of Microencapsulation is a well-established dedicated to the preparation, properties and uses of
individually encapsulated novel small particles, as well as significant improvements to tried-and-tested techniques relevant to micro
and nano particles and their use in a wide variety of industrial, engineering, pharmaceutical, biotechnology and research applications.
Its scope extends beyond conventional microcapsules to all other small particulate systems such as self-assembling structures that
involve preparative manipulation. The review covers encapsulation materials, physics of release through the capsule wall and / or
desorption from carrier, techniques of preparation, many uses to which microcapsules are put.© 2011 IGJPS. All rights reserved.
KEYWORDS: Microencapsulation; Core Materials; Coating Materials.
Microencapsulation is a process by which solids, liquids or even gases may be enclosed in microscopic particles formation of thin
coatings of wall material around the substances. The process had its origin in the late 1930s as a cleaner substitute for carbon paper
and carbon ribbons as sought by the business machines industry. The ultimate development in the 1950s of reproduction paper and
ribbons that contained dyes in tiny gelatin capsules released on impact by a typewriter key or the pressure of a pen or pencil was the
stimulus for the development of a host of microencapsulated materials, including drugs [1, 2].
A well designed controlled drug delivery system can overcome some of the problems of conventional therapy and enhance
the therapeutic efficacy of a given drug. To obtain maximum therapeutic efficacy, it becomes necessary to deliver the agent to the
target tissue in the optimal amount in the right period of time there by causing little toxicity and minimal side effects. There are
various approaches in delivering a therapeutic substance to the target site in a sustained controlled release fashion. One such approach
is using microspheres as carriers for drugs. Microspheres are characteristically free flowing powders consisting of proteins or synthetic
polymers which are biodegradable in nature and ideally having particle size less than 200 μm. Microencapsulation is a process by
which very tiny droplets or particles of liquid or solid material are surrounded or coated with a continuous film of polymeric material.
Microencapsulation includes Bio encapsulation which is more restricted to the entrapment of a biologically active substance (from
DNA to entire cell or group of cells for example) generally to improve its performance &/or enhance its shelf life [3, 4].
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INTRODUCTION

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Microencapsulation provides the means of converting liquids to solids, of altering colloidal and surface properties, of
providing environmental protection and of controlling the release characteristics or availability of coated materials. Several of these
properties can be attained by macro packaging techniques; however, the uniqueness of microencapsulation is the smallness of the
coated particles and their subsequent use and adaptation to a wide variety of dosage forms and not has been technically feasible.
Fig. 1: Microencapsulation process
This technique can be used for converting liquid drugs in a free flowing powder.
The drugs, which are sensitive to oxygen, moisture or light, can be stabilized by microencapsulation.
Incompatibility among the drugs can be prevented by microencapsulation.
Vaporization of many volatile drugs e.g. methyl salicylate and peppermint oil can be prevented by microencapsulation.
Many drugs have been microencapsulated to reduce toxicity and GI irritation including ferrous sulphate and KCl.
Alteration in site of absorption can also be achieved by microencapsulation.
Toxic chemicals such as insecticides may be microencapsulated to reduce the possibility of sensitization of factorial person.
Bakan and Anderson reported that microencapsulated vitamin A palmitate had enhanced stability.
The reasons for microencapsulation
The reasons for microencapsulation are countless. In some cases, the core must be isolated from its surroundings, as in isolating
vitamins from the deteriorating effects of oxygen, retarding evaporation of a volatile core, improving the handling properties of a
sticky material, or isolating a reactive core from chemical attack. In other cases, the objective is not to isolate the core completely but
to control the rate at which it leaves the microcapsule, as in the controlled release of drugs or pesticides. The problem may be as
simple as masking the taste or odor of the core, or as complex as increasing the selectivity of an adsorption or extraction process.

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Fig. 2: Microsphere & microcapsule
Fundamental considerations
The realization of the potential that microencapsulation offers involves a basic understanding of the general properties of
microcapsules, such as the nature of the core and coating materials, the stability and release characteristics of the coated materials and
the microencapsulation methods [5, 6].
Release mechanisms
Mechanisms of drug release from microspheres are
1. Degradation controlled monolithic system
The drug is dissolved in matrix and is distributed uniformly throughout. The drug is strongly attached to the matrix and is released
on degradation of the matrix. The diffusion of the drug is slow as compared with degradation of the matrix.
2. Diffusion controlled monolithic system
Here the active agent is released by diffusion prior to or concurrent with the degradation of the polymer matrix. Rate of release
also depend upon where the polymer degrades by homogeneous or heterogeneous mechanism.
3. Diffusion controlled reservoir system
Here the active agent is encapsulated by a rate controlling membrane through which the agent diffuses and the membrane erodes
only after its delivery is completed. In this case, drug release is unaffected by the degradation of the matrix.
4. Erosion
Erosion of the coat due to pH and enzymatic hydrolysis causes drug release with certain coat material like glyceryl mono
stearate, beeswax and steryl alcohol etc. [7-9].
Core materials
The core material, defined as the specific material to be coated, can be liquid or solid in nature. The composition of the core material
can be varied, as the liquid core can include dispersed and/or dissolved materials. The solid core be active constituents, stabilizers,
diluents, excipients, and release-rate retardants or accelerators. The ability to vary the core material composition provides definite

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flexibility and utilization of these characteristics often allows effectual design and development of the desired microcapsule properties
[10].
Coating materials
The selection of appropriate coating material decides the physical and chemical properties of the resultant
microcapsules/microspheres. While selecting a polymer the product requirements ie. Stabilization, reduced volatility, release
characteristics, environmental conditions, etc. should be taken into consideration. The polymer should be capable of forming a film
that is cohesive with the core material. It should be chemically compatible, non-reactive with the core material and provide the desired
coating properties such as strength, flexibility, impermeability, optical properties and stability.
Generally hydrophilic polymers, hydrophobic polymers (or) a combination of both are used for the microencapsulation
process. A number of coating materials have been used successfully; examples of these include gelatin, polyvinyl alcohol, ethyl
cellulose, cellulose acetate phthalate and styrene maleic anhydride. The film thickness can be varied considerably depending on the
surface area of the material to be coated and other physical characteristics of the system [11]. The microcapsules may consist of a
single particle or clusters of particles. After isolation from the liquid manufacturing vehicle and drying, the material appears as a free
flowing powder. The powder is suitable for formulation as compressed tablets, hard gelatin capsules, suspensions, and other dosage
forms.
The coating material should be capable of forming a film that is cohesive with the core material; be chemically compatible
and nonreactive with the core material; and provide the desired coating properties, such as strength, flexibility, impermeability, optical
properties, and stability. The coating materials used in microencapsulation methods are amenable, to some extent, to in situ
modification [12].
The selection of a given coating often can be aided by the review of existing literature and by the study of free or cast films,
although practical use of free-film information often is impeded for the following reasons:
Cast or free films prepared by the usual casting techniques yield films that are considerably thicker than those produced by
the microencapsulation of small particles; hence, the results obtained from the cast films may not be extrapolate to the thin
microcapsule coatings.
The particular microencapsulation method employed for the deposition of a given coating produces specific and inherent
properties that are difficult to simulate with existing film-casting methods.
The coating substrate of core material may have a decisive effect on coating properties. Hence, the selection of a particular
coating material involves consideration of both classic free-film data and applied results [13].
Coating material properties
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.
Examples of coating materials:
Water soluble resins – Gelatin, Gum Arabic, Starch, Polyvinylpyrrolidone, Carboxymethylcellulose, Hydroxyethylcellulose,
Methylcellulose, Arabinogalactan, Polyvinyl alcohol, Polyacrylic acid.

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Water insoluble resins – Ethylcellulose, Polyethylene, Polymethacrylate, Polyamide (Nylon), Poly (Ethylene Vinyl acetate),
cellulose nitrate, Silicones, Poly lactideco glycolide.
Waxes and lipids – Paraffin, Carnauba, Spermaceti, Beeswax, Stearic acid, Stearyl alcohol, Glyceryl stearates.
Enteric resins – Shellac, Cellulose acetate phthalate, Zein [14].
Techniques to manufacture microcapsules
Preparation of microspheres should satisfy certain criteria:
The ability to incorporate reasonably high concentrations of the drug.
Stability of the preparation after synthesis with a clinically acceptable shelf life.
Controlled particle size and dispersability in aqueous vehicles for injection.
Release of active reagent with a good control over a wide time scale.
Biocompatibility with a controllable biodegradability and Susceptibility to chemicalmodification [15].
Fig. 3: Microencapsulation techniques
Physical methods
Air-suspension coating
Microencapsulation by air suspension technique consist of the dispersing of solid, particulate core materials in a supporting air stream
and the spray coating on the air suspended particles. Within the coating chamber, particles are suspended on an upward moving air
stream. The design of the chamber and its operating parameters effect a recirculating flow of the particles through the coating zone
portion of the chamber, where a coating material, usually a polymer solution, is spray applied to the moving particles.
During each pass through the coating zone, the core material receives an increment of coating material. The cyclic process is
repeated, perhaps several hundred times during processing, depending on the purpose of microencapsulation the coating thickness

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desired or whether the core material particles are thoroughly encapsulated. The supporting air stream also serves to dry the product
while it is being encapsulated. Drying rates are directly related to the volume temperature of the supporting air stream.
Air-suspension coating of particles by solutions or melts gives better control and flexibility. The particles are coated while
suspended in an upward-moving air stream. They are supported by a perforated plate having different patterns of holes inside and
outside a cylindrical insert.
Just sufficient air is permitted to rise through the outer annular space to fluidize the settling particles. Most of the rising air
(usually heated) flows inside the cylinder, causing the particles to rise rapidly. At the top, as the air stream diverges and slows, they
settle back onto the outer bed and move downward to repeat the cycle. The particles pass through the inner cylinder many times in a
few minutes methods.
The air suspension process offers a wide variety of coating materials candidates for microencapsulation. The process has the
capability of applying coatings in the form of solvent solutions, aqueous solution, emulsions, dispersions or hot melts in equipment
ranging in capacities from one pound to 990 pounds. Core materials comprised of micron or submicron particles can be effectively
encapsulated by air suspension techniques, but agglomeration of the particles to some larger size is normally achieved.
Coacervation and microencapsulation
Coacervation is a colloid phenomenon. If one starts with a solution of a colloid in an appropriate solvent, then according to the nature
of the colloid, various changes can bring about a reduction of the solubility of the colloid. As a result of this reduction a large part of
the colloid can be separated out into a new phase. The original one phase system becomes two phases. One is rich and the other is
poor in colloid concentration. The colloid-rich phase in a dispersed state appears as amorphous liquid droplets called coacervate
droplets. Upon standing these coalesce into one clear homogenous colloid-rich liquid layer, known as the coacervate layer which can
be deposited so as to produce the wall material of the resultant capsules.
Coacervation may be initiated in a number of different ways. Examples are changing the temperature, changing the pH or
adding a second substance such as a concentrated aqueous ionic salt solution or a non-solvent.
As the coacervate forms, it must wet the suspended core particles or core droplets and coalesce into a continuous coating for the
process of microencapsulation to occur. The final step for microencapsulation is the hardening of the coacervate wall and the isolation
of the microcapsules, usually the most difficult step in the total process [16].
This process of microencapsulation is generally referred to The National Cash Register (NCR) Corporation and the patents of
B.K. Green. This process consists of three
Steps-
• Formation of three immiscible phases; a liquid manufacturing phase, a core material phase and a coating material phase
• Deposition of the liquid polymer coating on the core material
• Rigidizing of the coating material
Step-1: The first step of coacervation phase separation involves the formation of three immiscible chemical phases: a liquid
vehicle phase, a coating material phase and a core material phase. The three phases are formed by dispersing the core material in a
solution of coating polymer, the vehicle phase is used as a solvent for polymer. The coating material phase consists of a polymer in a
liquid phase, is formed by using one of the of phase separation- coacervation method, i.e. .by changing the temperature of the polymer
solution, by adding a solution, or by inducing a polymer- polymer interaction.
Step-2: It involves the deposition of the liquid polymer coating upon the core material. This is done by controlled mixing of
liquid coating material and the core material in the manufacturing vehicle. The liquid coating polymer deposited on the core material
if the polymer is adsorbed at the interface formed between the core material and liquid phase. The reduction in the total free interfacial

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energy of the system help to promote the deposition of the coating material, brought by the decrease of the coating material surface
area during coalescence of the liquid polymer droplets.
Step-3: In the last step rigidizing of the coating material done by the thermal, cross linking desolvation techniques, to forms a
self supporting microcapsule.
Fig. 4: Coacervation process: (a) Core material dispersion in solution of shell polymer; (b) Separation of coacervate from solution;
(c) Coating of core material by micro droplets of coacervate; (d) Coalescence of coacervate to form continuous shell around core
particles.
Simple coacervation
Simple coacervation involves the use of either a second more-water soluble polymer or an aqueous non-solvent for the gelatin. This
produces the partial dehydration/desolvation of the gelatin molecules at a temperature above the gelling point. This results in the
separation of a liquid gelatin-rich phase in association with an equilibrium liquid (gelatin-poor) which under optimum separation
conditions can be almost completely devoid of gelatin.
Simple coacervation can be effected either by mixing two colloidal dispersions, one having a high affinity for water, or it can
be induced by adding a strongly hydrophilic substance such as alcohol or sodium sulfate [17]. The water soluble polymer is
concentrated in water by the action of a water miscible, non-solvent for the emerging polymer (gelatin) phase. Ethanol, acetone,
dioxane, isopropanol and propanol have been used to cause separation of coacervate of gelatin, polyvinyl alcohol and methyl
cellulose. Phase separation can be effected by the addition of an electrolyte such as an inorganic salt to an aqueous solution of a
polymer such as gelatin, polyvinyl alcohol or carboxymethyl cellulose.
A typical simple coacervation using gelatin colloid is as follows: to a 10 percent dispersion of gelatin in water, the core
material is added with continuous stirring and at a temperature of 40°C. Then a 20 percent sodium sulfate solution or ethanol is added
at 50 to 60 percent by final total volume, in order to induce the coacervation. This system is cooled to 50°C; then, it is necessary to
insolubilize the coacervate capsules suspended in the equilibrium liquid by the addition of a hardening agent such as glutaraldehyde
and adjusting the pH. The resulting microcapsules are washed, dried and collected [18].

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Complex coacervation
Complex coacervation' can be induced in systems having two dispersed hydrophilic colloids of opposite electric charges.
Neutralization of the overall positive charges on one of the colloids by the negative charge on the other is used to bring about
separation of the polymer-rich complex coacervate phase.
The gelatin-gum arabic (gum acacia) system is the most studied complex coacervation system. Complex coacervation is
possible only at pH values below the isoelectric point of gelatin. It is at these pH values that gelatin becomes positively charged, but
gum arabic continues to be negatively charged. A typical complex coacervation process using gelatin and gum arabic colloids is as
follows: The core material is emulsified or suspended either in the gelatin or gum arabic solution. The aqueous solution of both the
gelatin and gum arabic should each be below 3 percent by weight. Then, the gelatin or the gum arabic solution (whichever was not
previously used to suspend the core material) is added into the system. The temperature of the system must be higher than the gel
point of an aqueous gelatin solution (greater than 35°C). The pH is adjusted to 3.8-4.3 and continuous mixing is maintained
throughout the whole process. The system is cooled to 50°C and the gelled coacervate capsule walls are insolubilized by either adding
glutaraldehyde or another hardening agent or adjusting the pH. The microcapsules are washed, dried and collected [19, 20].
Aqueous phase separation
The term aqueous phase separation is often more simply described as "oil-in-water" microencapsulation. The two encapsulation
processes described above are examples of this "oil-in-water" encapsulation. In this process the core material is the oil and it should be
immiscible in the continuous phase, namely water. A commercial example of aqueous phase separation would be the
microencapsulation of an oily flavor such as sour cream with a gelatin wall. These microcapsules would then be dispersed in a dry
cake mix. The mechanism of release would be during the moist baking cycle of the cake, moist-heat causing the capsule walls to first
swell and then rupture [21].
Organic phase separation
The term organic phase separation' is sometimes more simply referred to as "water-in-oil" microencapsulation. In this case the polar
core is dispersed into an oily or non-polar continuous medium. The wall material is then dissolved in this continuous medium. A
simple technique for encapsulation consists of dissolving ethyl cellulose in cyclohexane at a temperature of 50°C with continuing
mixing. Only one phase is present. The cyclohexane is the oily, continuous phase and the ethyl cellulose will later form the
coacervative wall. The temperature is elevated to 70°C over a period of 20 to 30 minutes. The core material is added and the
temperature raised to 80°C over a period of time and is held at that temperature for one hour. The system is allowed to cool rapidly to
20-40°C. Upon cooling, the ethyl cellulose will gradually emerge as a separated coacervate phase which will then gradually solidify
by the time 20°C is reached (unlike hot cyclohexane, the cold material is a non-solvent). The capsules are washed, filtered and air
dried. It should be noted that ethyl cellulose is generally approved for use in the pharmaceutical industry. However, for its use in the
food industry the "Code of Federal Regulations" should be consulted under the categories of both microencapsulation and ethyl
cellulose [22].
Another ethyl cellulose wall encapsulation system involves the addition of polyisobutylene to the ethyl
cellulose/cyclohexane. The procedure begins with the addition of ethyl cellulose to a mixture of cyclohexane and polyisobutylene at
room temperature. Polyisobutylene, which is more soluble in cyclohexane than is ethyl cellulose, is more effective in causing the latter
to emerge as a separate liquid coacervate than would be the case with merely cooling the cyclohexane. The solution is then heated to
80°C and the core material added. The system is cooled to 40°C in 60 minutes and cooled quickly to 20-25°C. Microcapsules are
filtered, washed and dried. A modification of this system involves the following procedure: The polyisobutylene is dissolved in
cyclohexane at a temperature of 700°C and with continuous stiffing. After cooling the system to 40°C, ethyl cellulose is added and

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dissolved. The core is dispersed in this solution and the system again heated to 78°C and held for 10 minutes at this temperature. Then
it is slowly cooled to room temperature followed by cooling to 10°C over two hours. Besides polyisobutylene, other coacervation
inducing agents have been used such as polyethylene and butyl rubber [23].
Designing the process--process and material selection
Coacervation is a very complicated physical phenomenon. And, many factors affect the properties of the resulting microcapsules.
Coacervation and phase separation from organic and aqueous media involve many properties, materials and processes such as: phase
inducing agents, stirring rates, core to wall ratios, polymer characteristics, core characteristics (wet ability, solubility), cooling rates
and rates of addition.
The basic production of microcapsules actually involves three distinct steps as discuss above. The hardening of the
microcapsules sufficient for isolation of them into a dry free-flowing powder remains as a persistent problem. One of the earliest
attempts is the gelatin-tannin reaction. Tannic acid is recognized as a means for "hardening" gelatin walled capsules. It should be
noted that a particular encapsulation system, such as would be described in any one of the patents in the literature, is not necessarily
effective in encapsulating a given flavor. Consequently it is often necessary to develop or modify an encapsulation system for each
flavor. This is particularly true when one looks at the multitude of requirements related to storage and release of the microcapsule core
[24]. Example: Coacervation Microencapsulation of Talc Particles with Poly (methyl methacrylate) by Pressure-Induced Phase
Separation of CO2-Expanded Ethanol Solutions
Polymer encapsulation by rapid expansion of supercritical fluids
Supercritical fluids are highly compressed gasses that possess several advantageous properties of both liquids and gases. These fluids
have attracted much attention in recent years, the most widely used being supercritical CO2, alkanes (C2to C4), and nitrous oxide
(N2O). They have low hydrocarbon-like solubility for most solutes and are miscible with common gases such as hydrogen (H2) and
nitrogen. A small change in temperature or pressure causes a large change in the density of supercritical fluids near the critical point a
property which enhances their use in several industrial applications. Supercritical CO2is widely used for its low critical temperature
value, in addition to its nontoxic, non flammable properties; it is also readily available, highly pure and cost-effective. It has found
applications in encapsulating active ingredients by polymers. Different core materials such as pesticides, pigments, pharmaceutical
ingredients, vitamins, flavors, and dyes are encapsulated using this method. A wide variety of shell materials that either dissolve
(paraffin wax, acrylates, polyethylene glycol) or do not dissolve (proteins, polysaccharides) in supercritical CO2are used for
encapsulating core substances [25].
The most widely used methods are as follows:
• Rapid expansion of supercritical solution (RESS)
• Gas anti-solvent (GAS)
• Particles from gas-saturated solution (PGSS)
Rapid expansion of supercritical solution
In this process, supercritical fluid containing the active ingredient and the shell material are maintained at high pressure and then
released at atmospheric pressure through a small nozzle. The sudden drop in pressure causes desolvation of the shell material, which is
then deposited around the active ingredient (core) and forms a coating layer. The disadvantage of this process is that both the active
in- gradient and the shell material must be very soluble in supercritical fluids. In general, very few polymers with low cohesive energy
densities (e.g., polydimethylsiloxanes, polymethacrylates) are soluble in supercritical fluids such as CO2. The solubility of polymers
can be enhanced by using co-solvents. In some cases nonsolvents are used; this increases the solubility in supercritical fluids, but the
shell materials do not dissolve at atmospheric pressure. A schematic of the microencapsulation process using supercritical CO2

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It had very recently carried out microencapsulation of TiO2nanoparticles with polymer by RESS using ethanol as a non solvent for the
polymer shell such as polyethylene glycol (PEG), poly(styrene)-b-(polymethyl methacrylate)-copoly(glycidal methacrylate)
copolymer (PS-b-(PMMA-co-PGMA) and polymethyl methacrylate) [26].
Gas anti-solvent (GAS) process
This process is also called supercritical fluid anti-solvent (SAS). Here, supercritical fluid is added to a solution of shell material and
the active ingredients and maintained at high pressure. This leads to a volume expansion of the solution that causes super saturation
Fig. 5: Microencapsulation by rapid expansion of supercritical solutions
such that precipitation of the solute occurs. Thus, the solute must be soluble in the liquid solvent, but should not dissolve in the
mixture of solvent and supercritical fluid. On the other hand, the liquid solvent must be miscible with the supercritical fluid. This
process is unsuitable for the encapsulation of water-soluble ingredients as water has low solubility in supercritical fluids. It is also
possible to produce submicron particles using this method [27].
Particles from a gas-saturated solution (PGSS)
This process is carried out by mixing core and shell materials in supercritical fluid at high pressure. During this process supercritical
fluid penetrates the shell material, causing swelling. When the mixture is heated above the glass transition temperature the polymer
liquefies. Upon releasing the pressure, the shell material is allowed to deposit onto the active ingredient. In this process, the core and
shell materials may not be soluble in the supercritical fluid. Within the pharmaceutical industry, preformed microparticles are often
used for the entrapment of active materials using supercritical fluids under pressure.
When the pressure is released, the microparticles shrink and return to their original shape and entrap the ingredients [28].
Centrifugal extrusion
Liquids are encapsulated using a rotating extrusion head containing concentric nozzles. In this process, a jet of core liquid is
surrounded by a sheath of wall solution or melt. As the jet moves through the air it breaks, owing to Rayleigh instability, into droplets
of core, each coated with the wall solution. While the droplets are in flight, a molten wall may be hardened or a solvent may be
evaporated from the wall solution. Since most of the droplets are within ± 10% of the mean diameter, they land in a narrow ring
around the spray nozzle. Hence, if needed, the capsules can be hardened after formation by catching them in a ring-shaped hardening
bath. This process is excellent for forming particles 400–2,000 μm (16-79 mils) in diameter. Since the drops are formed by the
breakup of a liquid jet, the process is only suitable for liquid or slurry. A high production rate can be achieved, i.e., up to 22.5 kg (50
lb) of microcapsules can be produced per nozzle per hour per head. Heads containing 16 nozzles are available [29].

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Pan coating
The pan coating process, widely used in the pharmaceutical industry, is among the oldest industrial procedures for forming small,
coated particles or tablets. The particles are tumbled in a pan or other device while the coating material is applied slowly. The pan
coating process, widely used in the pharmaceutical industry, is among the oldest industrial procedures for forming small, coated
particles or tablets.
Fig. 6: Representation of typical Pan Coating
The particles are tumbled in a pan or other device while the coating material is applied slowly with respect to microencapsulation,
solid particles greater than 600 microns in size are generally considered essential for effective coating, and the process has been
extensively employed for the preparation of controlled - release beads. Medicaments are usually coated onto various spherical
substrates such as nonpareil sugar seeds, and then coated with protective layers of various polymers.
In practice, the coating is applied as a solution, or as an atomized spray, to the desired solid core material in the coating pans.
Usually, to remove the coating solvent, warm air is passed over the coated materials as the coatings are being applied in the coating
pans. In some cases, final solvent removal is accomplished in a drying oven [30].
Fig. 7: List of variables affecting pan coating
Spray–drying
Spray drying serves as a microencapsulation technique when an active material is dissolved or suspended in a melt or polymer
solution and becomes trapped in the dried particle. The main advantages is the ability to handle labile materials because of the short
contact time in the dryer, in addition, the operation is economical. In modern spray dryers the viscosity of the solutions to be sprayed
can be as high as 300 m Pa.s.

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Spray drying and spray congealing processes are similar in that both involve dispersing the core material in a liquefied
coating substance and spraying or introducing the core coating mixture into some environmental condition, whereby, relatively rapid
solidification (and formation) of the coating is affected. The principal difference between the two methods is the means by which
coating solidification is accomplished. Coating solidification in the case of spray drying is effected by rapid evaporation of a solvent
in which the coating material is dissolved. Coating solidification in spray congealing methods, however, is accomplished by thermally
congealing a molten coating material or by solidifying a dissolved coating by introducing the coating - core material mixture into a
non-solvent. Removal of the non-solvent or solvent from the coated product is then accomplished by sorption, extraction, or
evaporation techniques.
In practice, microencapsulation by spray drying is conducted by dispersing a core material in a coating solution, in which the
coating substance is dissolved and in which the core material is insoluble, and then by atomizing the mixture into air stream. The air,
usually heated, supplies the latent heat of vaporization required to remove the solvent from the coating material, thus forming the
microencapsulated product [31].
Fig. 8: Spray Dryer
The equipment components of a standard spray dryer include an air heater, atomizer, main spray chamber, blower or fan,
cyclone and product collector. Microencapsulation by spray congealing can be accomplished with spray drying equipment when the
protective coating is applied as a melt. General process variables and conditions are quite similar to those already described, except
that the 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. Waxes,
fatty acids and alcohols, polymers and sugars, which are solids at room temperature but meltable at reasonable temperatures, are
applicable to spray congealing techniques. Typically, the particle size of spray congealed products can be accurately controlled when

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13
spray drying equipment is used, and has been found to be a function of the feed rate, the atomizing wheel velocity, dispersion of feed
material viscosity, and variables [32].
Airflow
The initial contact between spray droplets and drying air controls evaporation rates and product temperatures in the dryer. There are
three modes of contact:
Co-current
Drying air and particles move through the drying chamber in the same direction. Product temperatures on discharge from the dryer are
lower than the exhaust air temperature, and hence this is an ideal mode for drying heat sensitive products. When operating with rotary
atomizer, the air disperser creates a high degree of air rotation, giving uniform temperatures throughout the drying chamber. However,
an alternative non-rotating airflow is often used in tower or FILTERMAT-type spray dryers using nozzle atomizers with equal
success.
Counter-current
Drying air and particles move through the drying chamber in opposite directions. This mode is suitable for products which require a
degree of heat treatment during drying. The temperature of the powder leaving the dryer is usually higher than the exhaust air
temperature.
Mixed-flow
Particle movement through the drying chamber experiences both co-current and counter-current phases. This mode is suitable for heat
stable products where coarse powder requirements necessitate the use of nozzle atomizers, spraying upwards into an incoming airflow,
or for heat sensitive products where the atomizer sprays droplets downwards towards an integrated fluid bed and the air inlet and
outlet are located at the top of the drying chamber, eg. Study on microencapsulation of lycopene by spray drying [33].
Fluidized-bed technology
With the high demand for encapsulated materials in the global market, fluid-bed coaters have become more popular. They are used for
encapsulating solid or porous particles with optimal heat exchange. The liquid coating is sprayed onto the particles and the rapid
evaporation helps in the formation of an outer layer on the particles. The thickness and formulations of the coating can be obtained as
desired [34].
Different types of fluid-bed coaters include top spray, bottom spray, and tangential spray
(a) Top spray
(b) Bottom spray
(c) Tangential spray.
In the top spray system the coating material is sprayed downwards on to the fluid bed such that as the solid or porous particles move
to the coating region they become encapsulated. Increased encapsulation efficiency and the prevention of cluster formation is achieved
by opposing flows of the coating materials and the particles. Dripping of the coated particles depends on the formulation of the coating
material. Top spray fluid-bed coaters produce higher yields of encapsulated particles than either bottom or tangential sprays.
The bottom spray is also known as “Wurster’s coater” in recognition of its development by Prof. D.E. Wurster. This technique uses a
coating chamber that has a cylindrical nozzle and a perforated bottom plate. The cylindrical nozzle is used for spraying the coating
material. As the particles move upwards through the perforated bottom plate and pass the nozzle area, they are encapsulated by the
coating material.

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14
Fig. 9: Fluid bed coaters
The coating material adheres to the particle surface by evaporation of the solvent or cooling of the encapsulated particle. This process
is continued until the desired thickness and weight is obtained. Although it is a time consuming process, the multilayer coating
procedure helps in reducing particle defects [35].
The tangential spray consists of a rotating disc at the bottom of the coating chamber, with the same diameter as the chamber.
During the process the disc is raised to create a gap between the edge of the chamber and the disc. The tangential nozzle is placed
above the rotating disc through which the coating material is released. The particles move through the gap into the spraying zone and
are encapsulated. As they travel a minimum distance there is a higher yield of encapsulated particles [36].
Chemical methods
Solvent evaporation
This technique has been used by companies including the NCR Company, Gavaert Photo Production NV, and Fuji Photo Film Co.,
Ltd. to produce microcapsules. The processes are carried out in a liquid manufacturing vehicle. The microcapsule coating is dissolved
in a volatile solvent, which is immiscible with the liquid manufacturing vehicle phase. A core material to be microencapsulated is
dissolved or dispersed in the coating polymer solution. With agitation, the core coating material mixture is dispersed in the liquid
manufacturing vehicle phase to obtain the appropriate size microcapsule. The mixture is then heated (if necessary) to evaporate the
solvent for the polymer. 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. Once all the
solvent for the polymer is evaporated, the liquid vehicle temperature is reduced to ambient temperature (if required) with continued
agitation. At this stage, the microcapsules can be used in suspension form, coated on to substrates or isolated as powders.
The solvent evaporation technique to produce microcapsules is applicable to a wide variety of liquid and solid core materials.
The core materials may be either water soluble or water insoluble materials. A variety of film forming polymers can be used as
coatings [37]. Example: Evaluation of sucrose esters as alternative surfactants in microencapsulation of proteins by the solvent
evaporation method [38].
Polymerization
In this technique the capsule shell will be formed at or on the surface of the droplet or particle by polymerization of the reactive
monomers. The substances used are multifunctional monomers. Generally used monomers include multifunctional isocyanates and
multifunctional acid chlorides. These will be used either individually or in combination. The multifunctional monomer dissolved in
liquid core material and it will be dispersed in aqueous phase containing dispersing agent. A coreactant multifunctional amine will be
added to the mixture. This results in rapid polymerization at interface and generation of capsule shell takes place. A poly urea shell

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15
will be formed when isocyanate reacts with amine, polynylon or polyamide shell will be formed when acid chloride reacts with amine.
When isocyanate reacts with hydroxyl containing monomer produces polyurethane shell. Like IFP the capsule shell formation occurs
because of polymerization monomers added to the encapsulation reactor. In this process no reactive agents are added to the core
material, polymerization occurs exclusively in the continuous phase and on the continuous phase side of the interface formed by the
dispersed core material and continuous phase. Initially a low molecular weight prepolymer will be formed, as time goes on the
prepolymer grows in size, it deposits on the surface of the dispersed core material there by generating solid capsule shell. Example:
encapsulation of various water immiscible liquids with shells formed by the reaction at acidic pH of urea with formaldehyde in
aqueous media [39].
Interfacial polymer
In Interfacial polymerization, the two reactants in a polycondensation meet at an interface and react rapidly. The basis of this method
is the classical Schotten Baumann reaction between an acid chloride and a compound containing an active hydrogen atom, such as an
amine or alcohol, polyesters, polyurea, polyurethane. Under the right conditions, thin flexible walls form rapidly at the interface. A
solution of the pesticide and a diacid chloride are emulsified in water and an aqueous solution containing an amine and a
polyfunctional isocyanate is added. Base is present to neutralize the acid formed during the reaction. Condensed polymer walls form
instantaneously at the interface of the emulsion droplets [40].
In-situ polymerization
In a few microencapsulation processes, the direct polymerization of a single monomer is carried out on the particle surface. In one
process, 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. The coating is uniform, even over sharp projections [41].
Matrix polymer
In a number of processes, a core material is imbedded in a polymeric matrix during formation of the particles. A simple method of this
type is spray-drying, in which the particle is formed by evaporation of the solvent from the matrix material. However, the
solidification of the matrix also can be caused by a chemical change. Using this phenomenon, Chang prepares microcapsules
containing protein solutions by incorporating the protein in the aqueous diamine phase. Chang has demonstrated the permselectivity,
by their ability to convert blood urea to ammonia, the enzyme remaining within the microcapsules when incorporated within an
extracorporeal shunt system. Numerous groups are utilizing polymerization techniques to accomplish microencapsulation. Examples
are the National Lead Corporation, Eurand Americ [42].
Application of microencapsulation
There are many reasons why drugs and related chemicals have been microencapsulated. The technology has been used widely in the
design of controlled release and sustained release dosage forms [43-45].

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16
Fig. 9: Applications of microencapsulation
To mask the bitter taste of drugs like Paracetamol, Nitrofurantoin etc.
Many drugs have been microencapsulated to reduce gastric and other G.I. tract irritations. Sustained release Aspirin
preparations have been reported to cause significantly less G.I. bleeding than conventional preparations.
A liquid can be converted to a pseudo-solid for easy handling and storage. eg. Eprazinone.
Hygroscopic properties of core materials may be reduced by microencapsulation eg. Sodium chloride.
Carbon tetra chlorides and a number of other substances have been microencapsulated to reduce their odor and volatility.
Microencapsulation has been employed to provide protection to the core materials against atmospheric effects, e.g. vitamin A
palmitate.
Separation of incompatible substance has been achieved by encapsulation.
Cell immobilization: In plant cell cultures, Human tissue is turned into bio-artificial organs, in continuous fermentation
processes.
Beverage production.
Protection of molecules from other compounds.
Drug delivery: Controlled release delivery systems.
Quality and safety in food, agricultural & environmental sectors.
Soil inoculation.
In textiles: means of imparting finishes.
Protection of liquid crystals.
Characterization of microcapsule
The characterization of the micro particulate carrier is an important phenomenon, 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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17
Sieve analysis
Separation of the microspheres into various size fractions can be determined by using a mechanical sieve shaker (Sieving machine,
Retsch, Germany). 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 the particles on the screen are weighed [46].
Morphology of microspheres
The surface morphologies of microspheres are examined by a scanning electron microscope (XL 30 SEM Philips, Eindhoven, and The
Netherlands). The microspheres are mounted onto a copper cylinder (10 mm in diameter, 10 mm in height) by using a double-sided
adhesive tape. The specimens are coated at a current of 10 mA for 4 min using an ion sputtering device (JFC-1100E, Jeol, Japan) [47].
Atomic force microscopy (AFM)
A Multimode Atomic Force Microscope from Digital Instrument is used to study the surface morphology of the microspheres. The
samples are mounted on metal slabs using double-sided adhesive tapes and observed under microscope that is maintained in a
constant-temperature and vibration-free environment [48].
Particle size
Particle size determination approximately 30 mg microparticles is redispersed in 2–3 ml distilled water, containing 0.1% (m/m) Tween
20 for 3 min, using ultrasound and then transferred into the small volume recirculating unit, operating at 60 ml/s. The microparticle
size can be determined by laser diffractometry using a Malvern Mastersizer X (Malvern Instruments, UK) [49.]
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 solvent.
Viscosity of the polymer solutions
The absolute viscosity, kinematic viscosity, and the intrinsic viscosity of the polymer solutions in different solvents can be measured
by a U-tube viscometer (viscometer constant at 400C is 0.0038 mm2/s/s) at 25 ± 0.10C in a thermostatic bath. The polymer solutions
are allowed to stand for 24 h prior to measurement to ensure complete polymer dissolution [50].
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 [51].
Bulk density
The microspheres fabricated are weighed and transferred to a 10-ml glass graduated cylinder. The cylinder is tapped using an auto trap
(Quantach- Rome, FL, USA) 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.
Capture efficiency
The capture efficiency of the microspheres or the percent entrapment can be determined by allowing washed microspheres to lyse. The
lysate is then subjected to the determination of active constituents as per monograph requirement. The percent encapsulation
efficiency is calculated using following equation:
% Entrapment = Actual content/Theoretical content x 100

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18
Angle of contact
The angle of contact is measured to determine the wetting property of a micro particulate carrier. It determines 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. Contact angle is
measured at 200° within a minute of deposition of microspheres [52].
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 have been
employed as a quality control procedure in pharmaceutical production, in product development etc. Sensitive and reproducible release
data derived from physico chemically and hydro dynamically defined conditions are necessary. 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 [53].
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 and the stirrer speed form 60-300 rpm
[54].
Dissolution apparatus
Standard USP or BP dissolution apparatus have been used to study in vitro release profiles using both rotating elements (paddle and
basket). Dissolution medium used for the study varied from 100-500 ml and speed of rotation from 50-100 rpm.
Advantages
Reliable means to deliver the drug to the target site with specificity, if modified, and to maintain the desired concentration at
the site of interest without untoward effects.
Solid biodegradable microspheres have the potential throughout the particle matrix for the controlled release of drug.
Microspheres received much attention not only for prolonged release, but also for targeting of anticancer drugs to the tumour.
The size, surface charge and surface hydrophilicity of microspheres have been found to be important in determining the fate
of particles in vivo.
Studies on the macrophage uptake of microspheres have demonstrated their potential in targeting drugs to pathogens residing
intracellularly [55].
Microencapsulation means packaging an active ingredient inside a capsule ranging in size from one micron to several millimeters. The
capsule protects the active ingredient from its surrounding environment until an appropriate time. Then, the material escapes through
the capsule wall by various means, including rupture, dissolution, melting or diffusion. Microencapsulation is both an art and a
science. There's no ONE way to do it, and each new application provides a fresh challenge. Solving these riddles requires experience,
skill and the mastery of many different technologies.
CONCLUSION

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19
1. Alagusundaram M, Chetty MS, Umashankari C. Microspheres as a Novel drug delivery system – A review. Int J Chem. Tech. 2009 12:
526-534.
2. Allen LV, Popovich NG, Ansel HC. Pharmaceutical Dosage Forms and Drug Delivery Systems. Delhi, India: BI Pubication, 2005, 8: 265.
3. Banker G S, Rhodes C T. Modern pharmaceutics. In Parma Publication, 2002, 121: 501-527.
4. Bungenburg de Jong, H.G., Proc. Acad. Sci, Amsterdam, 41 p. 646 (1938).
5. Berger HL. Ultrasonic Liquid Atomization. 1St edition Hyde Park, NY: Partridge Hill Publishers; 1998.
6. Blanco MD and Alonso MJ. Development and characterization of protein-loaded poly (lactideco-glycolide) nanospheres. Eur J Pharm
Biopharm, 1997, 43:287-294.
7. Brazel SC, Peppas NA. Modeling of drug release from swellable polymers. Eur J Pharm Biopharm, 2000, 49: 47–48.
8. Benita S, Donbrow M. Controlled drug delivery through microencapsulation, J. Pharm Sci, 1982, 71: 205–210
9. Cassidy, JP, Landcert NM, Quardos E. Controlled buccal delivery of buprenorphine. J.control .Rel, 1993, 25: 21-29.
10. Chein, YW and Novir M. Mucosal adhesive device for long acting delivery of pharmaceutical combinations in oral cavity. US patent
NO.5578315, 1996, 2: 52-55.
11. Chien YW, Corbo DC, Liv JC “Mucosal delivery of progestational Steroids from a Controlled release device: in vitro/in vivo relationship.”
Drug Dev.Ind.pharm, 1991, 17: 2269-2290.
12. Collins AE and Deasy PB. Bioadhesive lozenge for the improved delivery of cetypyridinium chloride J.pharm.sci, 1990, 79:116-120.
13. Dortune, B, Ozer L, Vyanik N. Development and in vitro Evaluation of buccoadhesive pindodlo tablet formulation. Drug Dev. Ind. Pharm,
1998, 24: 281-288.
14. Fabregas, JL and Garcia N. Invitro studies on buccoadhesive tablet formulations of hydrocortisone hemisuccinate. Drug Dev. Ind. Pharm,
1995, 21: 1689-1696.
15. Fang-Jing Wang, Chi-Hwa Wang. Sustained release of etanidazole from spray dried microspheres prepared by non halogenated solvents. J.
of Controlled Release. 2002, 81: 263–280.
16. Guo, JH. Bioadhesive polymer buccal patches for buprenorphine controlled delivery: formulation in vitro adhesive and release properties.
Drug Dev.Ind.pharm, 1994, 20: 315-325.
17. Gohel MC, Amin AF. Formulation optimization of controlled release diclofenac sodium microspheres using factorial design. J. of
Controlled Release, 1998, 51:115-122.
18. Gunder W, Lippold BH, Lippold BC. Release of drugs from ethyl cellulose microcapsules (diffusion pellets) with pore formers and pore
fusion. Euro J Pharm Sci, 1995, 3: 203–214.
19. Green B K and Schleicher L: US patent, 2800457, CA 1957, 51; 15842d 1957; 13-627.
20. Ghulam Murtaza, Mahmood Ahamd, Naveed Akhtar and Fatima Rasool. A comparative study of various microencapsulation techniques:
effect of polymer viscosity on microcapsule characteristics. Pak. J. Pharm. Sci.2009, 3:291-300.
21. Hausberger AG, Deluca PP. Characterization of biodegra- dable poly(D,Llactide-co-glycolide) polymers and micro- spheres J. Pharm.
Biomed. Anal, 1995, 13: 747–760.
22. Higuchi T: Mechanism of sustained action medication, theoretical analysis of rate of release of solid drugs dispersed in solidmatrices. J.
Pharm Sci, 1963, 52: 1145–1149.
23. Haznedar S, Dortue B. Preparation and in vitro evaluation of eudragit microspheres containing acetazolamide. Int J of Pharm, 2004, 269:
131–140.
24. Hora MS, Rana RK, Nunberg JH, Tice TR, Gilley RM and Hudson ME. Release of human serum albumin from PLGA microspheres.
Pharm Res, 1990, 7:1190-1194.
25. Ishida, M, Nambu N, Nagai T. Highly viscous gel ointment containing carbapol for application to the oral mucosa. Chem. pharm Bull.
1983, 31:4561.
26. Jackson, LS and Lee K. Microencapsulation and the food industry. Lebennsmittel-Wissenschaft Techonologie. Ret on Cont Rel, 1991, 5:
199-205.
27. Jegat C, Taverdet J L. Stirring speed influence study on microencapsulation process and the drug release from microcapsules. Polymer
Bulletin, 2000, 44: 345–351
28. Jain N K., Controlled and Novel drug delivery. CBS Publisher, 1997, pp 236-237.
29. Jian You, Fu-de Cui, Xu Han, Yongsheng Wang, Lei Yang, Ying-Wei Yu, Qing-po. Literature of Biointerfaces, 2006, pp 35-41
30. James S. Encylopedia of PharmaceuticalTechonology, 2005, 3: 1325-1333.
. Khawla A, Abu izza, Lucila Garcia-Contreras, Robert Lu D. Selection of better methed for the preparationof microspheres by
applyinghierarchy process. J. Pharm Sci 1996, 85:144-149.
31. Khawla A, Abu izza, Lucila Garcia-Contreras, Robert Lu D. Selection of better methed for the preparation of microspheres by applying
hierarchy process. J. Pharm Sci, 1996 , 85:572-575
32. . Kreitz M, Brannon-peppas L, Mathiowitz E. Microencapsulation Encyclopedia of controlled drug delivery. John Wiley Sons publishers,
1999, pp 493-553.
33. Kesting RE. Synthetic Polymeric Membranes, A Structural Perspective A Wiley-Interscience Publication, Wiley, 1985, 2nd Edition: 525.
34. Korsmeye RW, Gurny R, Doelker EM, Buri P, Peppas NA. Mechanism of solute release from porous hydrophilic polymers. Int J
Pharmacet, 1983, 15: 25–35.
REFERENCES

Indo Global Journal of Pharmaceutical Sciences, 2012; 2(1): 1-20
20
35. Lachman LA, Liberman HA, Kanig JL. The Theory and Practice of Industrial Pharmacy. Mumbai, India: Varghese Publishng House.
3:414-415.
36. Leon, L, Herbert AL, Joseph LK. The Theory and Practice of Industrial Pharmacy. Varghese Publishing House. 1990, 3: 412-428.
37. Lopez, CR, Portero A, Vila-Jato, JC, Alonso MJ. Design and Evaluation of Chitosan/Ethylcellulose mucoadhesive bilayered devices for
buccal drug delivery. J. Control. Re, 1998, 55: 143-152.
38. Li SP, Kowarski CR, Feld KM and Grim WM Recent advances in microencapsulation technology and equipment. Drug Dev. Ind. Pharm,
1988, 14: 353-376.
39. Lu W and Park TG, Protein release from poly (lactic-co-glycolic acid) microspheres: protein stability problems. PDA J Pharm Sci
Technol, 1995, 49:13-19.
40. Nagai T, Machida Y, Suzuki Y, Ikura H. Method & preparation for administration to the mucosa & preparation for administration to the
mucosa of the oral or nasal cavity US patent NO.4226848. 1980.
41. Nikhil K Sachan. Controlled drug delivery through microencapsulation. Assam India, Dibrugarh University 2005,1-3
42. Nack H, Microencapsulation techniques, application and problems. J.Soc.Cosmetic Chemists, 1970, 21:85-98.
43. Nokhodchi A, Zakeri-Milani P, Valizadeh H and Hassan-Zadeh D: Evaluation of microcapsules of acetyl salicylic acid prepared with
cellulose acetate phthalate, ethyl cellulose or their mixtures by an emulsion non-solvent addition technique Ars Pharmaceutical, 2002, 43:
135–147
44. O’Donnell PB, McGinity JW. Preparation of microspheres by solvent evaporation technique. Adv Drug Delivery Reviews, 1997, 28:25-42.
45. Pao-Chu Wua, Yaw-Bin Huanga, Jui- Sheng Changa, Ming-Jun Tsaib, Yi-Hung Tsaia. Design and evaluation of sustained release
microspheres of potassium chloride prepared by Eudragit. Euro. J. of Pharma. Sciences, 2003, 19: 115–122.
46. Parodi, B, Russo E, Caviglioli G, Cafaggi S, Binardi G. Development &characterization of a buccoadhesive dosage form of Oxydodone
hydrochloride. Drug Dev.Ind.pharm,1996, 22: 445-450.
47. Rao MRP, Borate SG, Thanki KC, Ranpise AA, Parikh GN. Development and in vitro evaluation of floating rosiglitazone maleate
microspheres Drug Dev Ind Pharm, 2009, 35: 834-842.
48. Reis MAA, Sinisterra RD, Belchior JD. An alternative approach based on artificial neural networks to study controlled drug release. J.
Pharma Sci, 2004, 93: 418–430.
49. Rowe, E.L. U.S. Patent 3 336 155, 1967.
50. Schugens C, Larvelle N, Nihantn S, Grandfils C, Jerome R, Teyssie P. P. J. Control. Rel, 1994, 32:161.
51. Tanaka W, Akito E, Yoshida K, Terada T, Ninomiya H. Pharmaceutical preparations for oral cavity administration. US patent No.
4059686. 1977.
52. Venkatesan P, Muralidharan C, Manavalan R, Valliappan K. Selection of better method for the preparation of microspheres by applying
Analytic Hierarchy Process. J. Pharm. Sci. & Res. 2009, 1: 64-78.
53. Venkatesh H. A buccal delivery system of Salbutamol Sulphate. J. Pharm. Sci. & Res. 1989, 3: 53-55
54. Vyas SP and Khar RK. Targeted and Controlled drug delivery, 07 Edition: 418.
55. Yi-Yan Yang, Hui-Hui Chia, Tai-Shung Chung. Effect of preparation temperature on the characteristics and release profiles of PLGA
microspheres containing protein fabricated by double-emulsion solvent extraction / evaporation method. J. Cont Rel. 2000, 69: 81–96.