INTRODUCTION:

Microencapsulation is a technique by which thin coatings of wall material are formed around the substances which may be solids, liquids or even gases, enclosed in microscopic particles. The origin of this technique is in the late 1930s as a cleaner substitute for carbon paper and carbon ribbons as sought by the business machines industry. In the 1950s, the paper and ribbons were developed that contained dyes in tiny gelatin capsules which were released on impact by a typewriter key or the pressure of a pen or pencil.

By delivering the agent to the target tissue in the optimal amount in the right period of time, maximum therapeutic efficacy, little toxicity and minimal side effects can be achieved. 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.¹

An appropriate motto for microencapsulation would be 'Small is better'. In its simplest form, a microcapsule is a small sphere with an uniform wall around it. The material inside the microcapsule is known as the core, fill, or internal phase, whereas the wall is called a shell, membrane or coating.²

Microspheres are considered as free flowing powders having biodegradable polymers. Microencapsulation process helps for controlling the release characteristics of different coated materials, converting the liquids to solids, changing the colloidal and surface properties and providing environmental protection. The advantage of microencapsulation is smallness of the coated particles and their subsequent use and adaptation to a wide variety of dosage forms and product application. Drug moieties can be widely distributed throughout the gastrointestinal tract, because of smallness of particles, thus potentially improving drug sorption.^{3, 4}Size of the microencapsulated products is considered as larger than 1micrometer and up to 1000 micrometers in diameter.⁵Commercially available microparticles contain 10-90% w/w core. In microencapsulation technology, the absorption rate of a drug can be controlled by controlling its rate of release from the dosage form.³

Core materials

It is the specific material to be coated, can be liquid or solid in nature. The liquid core can include dispersed and/or dissolved materials. The solid core can include active constituents, stabilizers, diluents, excipients and release-rate retardants or accelerators.¹ Number of core materials can be encapsulated like that live cells, adhesives, flavors, agrochemicals, enzymes, pharmaceuticals.³

Coating materials⁶

The physical and chemical properties of the resultant microcapsules/microspheres depend on the selection of coating materials. They may be hydrophilic polymers, hydrophobic polymers (or) a combination of both. A number of coating materials have been used successfully; examples of these include alginates⁷, gelatin, polyvinyl alcohol, ethyl cellulose, cellulose acetate. It should form a film that is cohesive with the core material.

Coating material properties^{6, 8}

· Controlled release under specific conditions.

· Stable towards core material.

· Inert toward active ingredients.

· Stable Film-forming, tasteless,

· Economical.

· The coating can be flexible, hard, thin etc.

· Soluble in an aqueous media or solvent, or melting.

Examples of coating materials: ^{9, 10,
11}

· Water soluble resins – Starch, Gelatin, Gum Arabic, Hydroxyethylcellulose Polyvinylpyrrolidone, Carboxymethylcellulose, Methylcellulose, Arabinogalactan, Polyvinyl alcohol, Polyacrylic acid.

· Water insoluble resins – Ethylcellulose, Polyethylene, Polymethacrylate, Polyamide (Nylon), Poly (Ethylene Vinyl acetate) and 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

Classification¹:

Microcapsules can be classified on three basic categories according to their morphology as follows,

1. Mononuclear

2. Polynuclear and

3. Matrix types

Mononuclear (core-shell) microcapsules contain the shell around the core, while polynuclear capsules have many cores enclosed within the shell. In matrix encapsulation, the core material is distributed homogeneously into the shell material. In addition to these three basic morphologies, microcapsules can also be mononuclear with multiple shells, or they may form clusters of microcapsules.

Figure 1: Microcapsule and microsphere

(a)

(b)

Figure 2: Various configurations of (a) microcapsules and (b) microspheres.

Table1: Terminology of microencapsulation products³⁰

Terminology	Description	Size range	Schematic illustration
Microcapsules	Contain the shell around the core e.g, coating liquid nuclei with solid walls.	μm
Nanocapsules	Same structure as microcapsules, but smaller.	nm
Microspheres or microparticles	The core material is distributed homogeneously into the shell material The cores and walls are both solid having no clear distinction between them	μm
Nanospheres or nanoparticles	Same structure as microspheres, but smaller.	nm
Liposomes Niosomes	Lipid wall often made of phospholipids and cholesterol. Subtypes: unilamellar (one lipid layer) and multilamellar (several lipid layers). Similar to liposomes but their membranes are made of synthetic amphiphylic molecules (Detergents).	μm to nm

Reasons for Microencapsulation ^1-9:

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. There are several reasons why substances may be encapsulated.²

1. To formulate a sustained or prolonged release of the drug.

2. To improve patient compliance by masking the unacceptable taste and odor.

3. To convert the liquid drugs in a free flowing powder.

4. To protect the drug from moisture, light and oxygen, e. g. Nifedipine

5. To prevent the incompatibility between drugs

6. To prevent the volatilization of drugs at room temperature like Aspirin and peppermint oil.

7. To reduce the toxicity and GI irritation produced with KCl and ferrous sulphate.

8. To change the site of absorption.

9. To isolate vitamins from the deteriorating effects of oxygen such as microencapsulated vitamin A palmitate had enhanced stability, as prevent from oxidation.

10. To prepare intrauterine contraceptive device.

11. To protect the immediate environment of the microcapsules from the active components.

12. To reduce the possibility of sensitization of factorial person such as insecticides.

Difficulties in Microencapsulation Technique:

· Incomplete or discontinuous coating

· Inadequate stability or shelf life of sensitive pharmaceuticals

· Non reproducible and unstable release characteristics of coated products

· Economic limitations

Microencapsulation Techniques: ^{5, 12,
13}

In general microencapsulation techniques are divided into two basic groups, namely chemical and physical, with the latter being further subdivided into physicochemical and physico-mechanical techniques. The techniques are shown in table 2:

Table2: Different techniques used for microencapsulation:

Chemical processes

Physical processes

Physico-chemical

Physico-mechanical

· Suspension, dispersion and emulsion polymerization

· Polycondensation

· Solvent evaporation method

· Coacervation

· Layer-by-layer (L-B-L) assembly

· Sol-gel encapsulation

· Supercritical CO₂-assisted microencapsulation

· Spray-drying

· Multiple nozzle spraying

· Fluid-bed coating

· Centrifugal techniques

· Vacuum encapsulation

Chemical Methods

In-situ processes such as emulsion, suspension, precipitation or dispersion polymerization and interfacial polycondensation are the most important chemical techniques used for microencapsulation.

Polymerization: ^{5, 12}

It is a new in situ method of microencapsulation. In polymerization a liquid or gaseous phase is used as continuous or core material and involved reaction between them. As a result the polymerization reaction occurs at a liquid-liquid, solid-liquid, Liquid-gas, or solid-gas interface and form protective microcapsule coatings.

Interfacial polymerization technique: ^{14, 15}

The microencapsulation of di-ammonium hydrogen phosphate (DAHP) by polyurethane-urea membrane was done using an interfacial polymerization method. Microcapsules are produced by the interfacial reaction of diphenyl methylene diisocyanate (MDI) which is dissolved in toluene and water at the interface of drops of the aqueous phase (containing DAHP) dispersed in the organic phase.

Interfacial polymerization method included the following steps:

(1) Dispersion of an aqueous solution (core material) in an oil phase,

(2) Addition of the wall-forming solution, and

(3) Growth of the membrane.

In the general procedure for the preparation of the microcapsules, the three solutions are used:

The organic phase (OP1) and the solution containing the core substance (W) are vigorously stirred using a homogenizer (8000 rpm) for 5 min at room temperature. The solution (OP2) of diisocyanate monomer (MDI) and catalyst (DBDL) is added to the primary emulsion. For the formation of the primary membrane, the mixture is stirred (700 rpm) for 10 min at room temperature. Then, stirring is reduced to 300 rpm and reaction lasts for 4 h allowing the membrane growth (63⁰C). The microcapsule slurry is decanted and washed with toluene and water to remove unreacted MDI and non-encapsulated DAHP. The filtered microcapsules are dried at 40⁰C for 24 h. The microcapsules are characterized by several techniques: elementary analysis, particle size distribution, FTIR spectroscopy, solid state NMR and thermal analysis.

Solvent evaporation method:^{16, 17, 18}

It consists of four major steps:

Figure 3: Basic steps of microencapsulation by solvent evaporation.

(1) Dissolution or dispersion of the drug in an organic solvent containing the polymer;

(2) emulsification of this organic phase, called dispersed phase, in an aqueous phase called continuous phase;

(3) Extraction of the solvent from the dispersed phase by the continuous phase, accompanied by solvent evaporation, transforming droplets of dispersed phase into solid particles; and

(4) Recovery and drying of microspheres to eliminate the residual solvent.

Other alternative methods of Solvent evaporation method:

The Other alternative methods of Solvent evaporation methods are shown below in figure 3

1. The w/o/w double emulsion method:

2. The o/w co-solvent method:

3. The o/w dispersion method:

4. The o/o non-aqueous solvent evaporation method

Physico-Chemical Methods:

Coacervation Method-^{6, 4, 19}

This process consists of three steps-

1. Formation of three immiscible phases

2. Deposition of the liquid polymer coating on the core material

3. Rigidizing of the coating material

Step-1: Formation of three immiscible phases

It involves the formation of three immiscible chemical phases: a liquid vehicle phase, a coating material phase and a core material phase.

Step-2: Deposition of the liquid polymer coating on the core material

It involves the controlled, physical mixing of the material in the manufacturing vehicle. The liquid polymer coating deposits upon the core material. Core material occurs if the polymer is adsorbed at the interface formed between the core material and the liquid vehicle phase, and this adsorption phenomenon is a prerequisite to effective coating.

Step-3: Rigidizing of the coating material

It involves rigidizing the coating material, usually by thermal, cross-linking or desolvation techniques, to form self-sustaining microcapsules.

Physico-Mechanical Methods:

Spray-Drying Method: ^{4, 20}

This method is conducted by dissolving coating material in which core material is insoluble and dispersed in it. Then the mixture is atomized into an air stream which is usually heated. This air supplies the latent heat of vaporization to remove solvent from coating material. Thus the microencapsulated product is formed.

For example, Tramadol was complexed with a sulfonic acid cation-exchange resin by a column method. Microencapsulation of tramadol–resin complexes (TRC) was carried out by the spray-drying method.

The TRC were suspended into various EC organic solutions with constant magnetic stirring, then subsequently spray-dried in a laboratory spray dryer through a two-fluid pressure nozzle with a concurrent drying air flow. It was found that with the proper selection of solvent and viscosity-grade provide satisfactory sustained-release for the tramadol–resin complex.

Pan coating: ^{4, 21}

The pan coating process is among the oldest industrial procedures for forming tablets and coated particles, widely used in the pharmaceutical industry. The particles are tumbled in a pan or other device while the coating material is applied slowly. For microencapsulation, solid particles greater than 600 microns in size are generally considered and are tumbled in a pan or other device and the coating material is applied slowly. The coating material is applied in the form of a solution, or as an atomized spray. The coating solvent is removed using warm air or drying in the oven.

In another way solid particles are mixed with a dry coating material. The temperature is raised so that the coating material melts and encloses the core particles, and then is solidified by cooling.

Co-Extrusion method:^{4, 21}

In this process, a jet of core liquid is surrounded by a sheath of wall solution or melt. A dual fluid stream of liquid core and shell materials is pumped through concentric tubes and forms droplets under the influence of vibration. The shell is then hardened by chemical cross linkings, cooling, or solvent evaporation. Different types of extrusion nozzles have been developed in order to optimize the process. The particles formed are in the range of 400– 2,000 μm (16–79 mils) in diameter. The drops are formed by the breakup of a liquid jet; therefore the process is only suitable for liquid or slurry.

Chemical crosslinking methods: ^{22, 23}

The primary amine groups of chitosan are reacted with different crosslinking agents like a di-aldehyde (mostly glutaraldehyde, formaldehyde). The aqueous solution of chitosan with the drug is added in a water-immiscible solvent (e.g. liquid paraffin) containing a surfactant and the water-in-oil (w/o) emulsion is formed, after which glutaraldehyde of varying amount is added depending upon the crosslinking density required. And thus drug-loaded microspheres are obtained. The microspheres formed are filtered, washed with suitable solvents and dried. It has also been reported that glutaraldehyde crosslinking leads to the formation of microspheres with rough surface which can be overcome by using toluene saturated glutaraldehyde.

Characterization/ Evaluation of Microspheres: ^{1, 4,
24, 25, 26,}

Sieve analysis

Mechanical sieve shaker is used to separate the microspheres into various size fractions. Five standard stainless steel sieves (20, 30, 45, 60 and 80 mesh) in a series are arranged in the order of decreasing aperture size. Drug loaded microspheres are placed on the upper-most sieve. The sieves are shaken for 10 min, and then the particles separated are weighed.

Morphology of microspheres

1. Optical microscopy:

This method is used to determine particle size by using optical microscope. The measurement is done under 100x (10x eye piece and 10x objective), 450x (10x eye piece and 45x objective) and 100 particles are calculated.

Microcapsule solvation can be predicted using following formula;

M1 - Microcapsules weighed immediately

M2 - After drying to a constant weight

2. Micromeritic properties:

a) Bulk density:

b) Tap density

Tap density is measured by employing the conventional tapping method or tap density apparatus using measuring cylinder and 100 tapings, taped density is calculated by following formula;

Compressibility index :

c) Hausnner’s ratio:

d) Angle of repose:

Accurately weighed microcapsules are passed through a funnel on the horizontal surface. The height (h) of the heap formed and radius (r) of cone base are measured. The angle of repose (θ) is calculated by following formula;

Where r is the radius and h is the height

3. Scanning electron microscopy (SEM):

SEM method is used to determine the surface morphology of microcapsule. With the help of double sided sticking tape, microcapsule are mounted directly on the SEM sample slub and coated with gold film under reduced pressure.

4. Microcapsule Percentage Yield :

Where M is the weight of microcapsules and Mo is the total expected weight of drug and polymer.

5. Drug Loading, and Encapsulation Efficiency:

Microspheres containing drug (20 mg) are crushed and then dissolve in distilled water with the help of ultrasonic stirrer for 3 hr, filter and assayed by UV-visible spectroscopy.

6. Swelling index: ⁴

Characterization of sodium alginate microspheres is performed with this technique. Alginate microspheres (100mg) are placed in a wire basket which is kept on the solution (100 ml) such as distilled water, buffer solution of pH (1.2, 4.5, 7.4) at 37⁰ C and changes in weight between initial weight of microspheres and weight due to swelling is measured by taking weight periodically and soaking with filter paper.

7. Thermal analysis:

Thermal analysis of microcapsule and its component can be done by using-

Differential scanning calorimetry (DSC)

Differential thermometric analysis (DTA)

Thermo gravimetric analysis (TGA)

8. X-ray diffraction

This technique is used to determine the change in crystallinity of drug.

9. Stability studies

The microspheres are placed in screw capped glass container and stored at conditions:

1. Ambient humid condition

2. Room temperature (27 +/- 2 ⁰C)

3. Oven temperature (40 +/- 2 ⁰C)

4. Refrigerator (5 ⁰C - 8⁰C).

It is carried out for 60 days and the drug content and drug release of the microsphere are analyzed.

Release Mechanisms ^{21, 27}

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.

Table 3: List of the Techniques Used For Encapsulation of Different Core Materials

Core material	Reason For Encapsulation	Coating agent	Technique used	reference
Ciprofloxacin	Taste Masking Of Bitter Drugs	Eudragit NE30D/RL30D, HPMC	Wurster fluid bed coating	8
Clarithromycin	Taste Masking Of Bitter Drugs	Glyceryl monostearate, Eudragit E100	Spray congealing	8
Chloroquine	Taste Masking Of Bitter Drugs	diphoshphate Eudragit RS100	Coacervation Phase seperation	8
Tramadol	Oral Sustained-Release	ethylcellulose	the spray-drying method	20
Cisplatin	Sustained Release	chitin and chitosan	w/o emulsion cross-linking method	22
Verapamil Hydrochloride	For Gastro Retention And Controlled Release	Methocel K4M, Methocel K15M and Methocel K100M	emulsion solvent evaporation technique	31
Loxoprofen	Sustained Release	Ethylcellulose,	Emulsion Solvent Evaporation Technique	32
Rifampicin (RIF)	Controlled Release	Eudragit	emulsion solvent diffusion method	33
Clarithromycin	For Gastro Retention	Eudragit S 100, RS 100, RL 100, L 100 and L 100 55	emulsion solvent diffusion method	34
Volatile Citronella Oil	Sustained Release	Chitosan	Modified Orifice Method	35
Repaglinide	Controlled Release To Increase Residence Time In The Stomach	Eudragit S	Emulsion Solvent Diffusion Technique	36
Garcinia fruit extract	For Protection And Controlled Release Of Food Ingredients Like (-) Hydroxycitric Acid (HCA)	whey protein isolate (WPI), maltodextrin (MD)	Freeze drying technique	37
potassium chloride	Sustained Release, Minimize The Gastric Irritation	Eudragit RS and RL	solvent evaporation method	38
metformin hydrochloride	Controlled Release	Pectins	water in oil (w\o) emulsion solvent evaporation technique	39
zedoary turmeric oil (ZTO)	Sustained Release	Hydroxypropyl methylcellulose acetate succinate (HPMCASHG), hydroxypropyl methylcellulose (HPMC-60SH4000)	quasi-emulsion–solvent-diffusion method	40
Clonazepam	Bioadhesive Drug Delivery System	Gelatin-Chitosan	-	41
Amoxicillin GI	Bioadhesive Drug Delivery System -Therapeutic Efficacy Of Drug Increases	Ethylcellulose-Carbopol- 934P	-	41

Application of Microencapsulation: ^{4, 6, 8, 15, 28}

1. General Application

1. Cell immobilization:

In plant cell cultures, Human tissue is turned into bio-artificial organs, in continuous fermentation processes.

2. Beverage production

3. Protection of molecules from other compounds:

4. Quality and safety in food, agricultural and environmental sectors.

5. Soil inoculation.

6. In textiles: means of imparting finishes.

7. Protection of liquid crystals

8. Most flavoring is volatile; therefore encapsulation of these components extends the shelf-life of products by retaining within the food flavours that would otherwise evaporate out and be lost. Some ingredients are encapsulated to mask taste, such as nutrients added to fortify a product without compromising the product’s intended taste

2. Controlled Release and Sustained Release Dosage Forms

It includes,

1. To mask the bitter taste of drugs like Paracetamol, Nitrofurantoin etc.

2. To reduce gastric and other gastro intestinal (G.I) tract irritations, e.g., sustained release Aspirin preparations have been reported to cause significantly less G.I. bleeding than conventional preparations.

3. A liquid can be converted to a pseudo-solid for easy handling and storage e.g. eprazinone.

4. Hygroscopic properties of core materials may be reduced by microencapsulation e.g., Sodium chloride.

5. Carbon tetrachloride and a number of other substances have been microencapsulated to reduce their odor and volatility.

6. Microencapsulation has been employed to provide protection to the core materials against atmospheric effects, e.g., Vitamin-A Palmitate.

7. Separation of incompatible substance has been achieved by encapsulation

8. Physicochemical evaluation characterization: The characterization of the microparticulate 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.

2. Medical application

1. Release of proteins, hormones and peptides over extended period of time.

2. Gene therapy with DNA plasmids and also delivery of insulin.

3. Vaccine delivery for treatment of diseases like hepatitis, influenza, pertusis, ricin toxoid, diphtheria, birth control.

4. Passive targeting of leaky tumour vessels, active targeting of tumour cells, antigens, by intraarterial/ intravenous application.

5. Tumour targeting with doxorubicin and also treatments of leishmaniasis.

Magnetic microspheres can be used for stem cell extraction and bone marrow purging.

6. Used in isolation of antibodies, cell separation, and toxin extraction by affinity

chromatography.

7. Used for various diagnostic tests for infectious diseases like bacterial, viral, and fungal.

3. Radioactive microsphere’s application

1. Can be used for radioembolisation of liver and spleen tumours.

2. Used for radiosynvectomy of arthiritis joint, local radiotherapy, interactivity treatement.

4. Cosmetics: ²⁹

For cosmetic applications, organic acids are usually good solvents; chitin and chitosan have fungicidal and fungistatic properties. Chitosan is the only natural cationic gum that becomes viscous on being neutralized with acid. These materials are used in creams, lotions and permanent waving lotions and several derivatives have also been reported as nail lacquers.

5. Photography: ²⁹

Chitosan has important applications in photography due to its resistance to abrasion, its optical characteristics, and film forming ability. Silver complexes are not appreciably retained by chitosan and therefore can easily be penetrated from one layer to another of a film by diffusion.

CONCLUSION:

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.

REFERENCES:

1. Agnihotri N et al. Microencapsulation – A Novel Approach in Drug Delivery: A Review, Indo Global Journal of Pharmaceutical Sciences, 2(1); 2012: 1-20.

2. Umer H et al. Microencapsulation: Process, Techniques and Applications, International Journal of Research in Pharmaceutical and Biomedical Sciences, 2 (2); 2011: 474-481.

3. Kumar A, Sharma PK and Banik A. Microencapsulation: As A Novel Drug Delivery System, Internationale Pharmaceutica Sciencia, l (1); 2011:1-7.

4. Bakan JA. Microencapsulation. The Theory and Practice of Industrial Pharmacy Edited by Lachman LA, Liberman HA, Kanig JL. Varghese Publishing House, Bombay.1987; 2nd ed: pp.414-420.

5. Jain N K., Controlled and Novel drug delivery. CBS Publisher, 1997, 236-237.

6. Radhika PR.et al. Preparation of Enteric Coated Beads by Coacervation Technique-A Review, International Journal of Pharmacy Review and Research, 2 (1); 2012: 53-60.

7. Cheong Hian Goh, Paul Wan Sia Heng, Lai Wah Chan, Alginates as a useful natural polymer for microencapsulation and therapeutic Applications, Carbohydrate Polymers, 88;2012:1–12.

8. Sharma S and Lewis S, Taste Masking Technologies: A Review, International Journal of Pharmacy and Pharmaceutical Sciences, 2(2); 2010: 6-13.

9. Jae Hyung Park, Mingli Ye and Kinam Park, Biodegradable Polymers for Microencapsulation of Drugs, Molecules 10; 2005: 146-161.

10. Roy S et al. Polymers in Mucoadhesive Drug Delivery System: A Brief Note, Designed monomers and polymers 12; 2009 : 483-495.

11. Chuanyun Daia, Bochu Wang, Hongwei Zhao, Microencapsulation peptide and protein drugs delivery system , Colloids and Surfaces B: Biointerfaces 41; 2005:117–120.

12. Vyas S P, Khar R K. Targeted and Controlled drug delivery. CBS Publisher, 2002, 418.

13. Diane J. Burgees and Anthony J. Hickey, Encyclopedia of pharmaceutical technology, microspheres technology and applications, 2^nd edition,2: 1783-1794.

14. Saihi D, Vroman I, S. Giraud, S. Bourbigot, Microencapsulation of ammonium phosphate with a polyurethane shell. Part II. Interfacial polymerization technique, Reactive and Functional Polymers 2006,66: 1118–1125

15. A. Attila Hincal and H. Suheyla Kas, Handbook of Pharmaceutical Controlled Release Technology; Microencapsulation Technology: Interfacial Polymerization Method, 271-286.

16. Ming Li, Olivier Rouaud, Denis Poncelet, Microencapsulation by solvent evaporation: State of the art for process engineering approaches, International Journal of Pharmaceutics, 363; 2008: 26–39.

17. Tiwari S, Verma P, Microencapsulation Technique by Solvent Evaporation Method (Study of Effect of Process Variables), International Journal of Pharmacy and Life Sciences, 2 (8); 2011:998-1005.

18. A. Attila Hincal and Sema Calis, Handbook of Pharmaceutical Controlled Release Technology; Microspheres prepared by solvent evaporation method, 329-344.

19. H. Suheyla Kas, Levent Oner, Handbook of Pharmaceutical Controlled Release Technology; Microencapsulation using co-acervation- phase separation and overview of the technology and applications, 301-328.

20. Zhi-Yan Zhang, Qi- Neng Ping , Bin Xiao, Microencapsulation and characterization of tramadol–resin complexes, Journal of Controlled Release 66; 2000:107–113.

21. Sharma N, Rathore KS, A Review on Microencapsulation: A New Multiutility Advanced Technology, International Journal of Advanced research in Pharmaceutical and Bio Sciences, 1 (4); 2012:477-489.

22. Sinha V.R et al. Chitosan microspheres as a potential carrier for drugs, International Journal of Pharmaceutics 274; 2004:1–33.

23. Kushwaha Swatantra K.S., Rai Awani K., Singh Satyawan, Chitosan: A Platform for Targeted Drug Delivery, International Journal of PharmTech Research, 4; 2010:2271-2282.

24. Haznedar S, Dortunc B, Preparation and in vitro evaluation of Eudragit microspheres containing acetazolamide, International Journal of Pharmaceutics, 269; 2004:131–140.

25. L Pachuau, S Sarkar and B Mazumder, Formulation and evaluation of matrix microspheres for simultaneous delivery of salbutamol sulphate and theophylline, Tropical Journal of Pharmaceutical Research, 7 (2); 2008: 995-1002.

26. Sebastien Gouin, Microencapsulation: industrial appraisal of existing technologies and trends, Trends in Food Science and Technology, 15; 2004:330–347.

27. Cassidy JP, Landcert NM, Quardos E. Controlled buccal delivery of buprenorphine. Journal of controlled Release, 25; 1993: 21-29.

28. Ansel, H. C., Pharmaceutical dosage form and drug delivery system. Lippincott Williams and Wilkins. 2000, 233-234.

29. Majeti N.V, Ravi Kumar, A review of chitin and chitosan applications, Reactive and Functional Polymers 46; 2000:1–27.

30. Bojana Boh, Bostjan Sumiga, Microencapsulation technology and its applications in building construction materials, RMZ – Materials and Geoenvironment, 55(3); 2008:329-344.

31. Patel MP et al. Microencapsulation of Verapamil Hydrochloride: A Novel Approach for Gastric Retention Using Different Polymers, Med chem, 2(4); 2012: 076-080.

32. Venkatesan. P, Manavalan. R and Valliappan. K, Preparation and evaluation of sustained release loxoprofen loaded microspheres, Journal of Basic and Clinical Pharmacy, 2(3); 2011:159-162.

33. Bhise SB, More AB, Malayandi RK, Formulation and In Vitro Evaluation of Rifampicin Loaded Porous Microspheres, Scientia Pharmaceutica, 78; 2010: 291–302.

34. Aphale S et al. Development And Evaluation of Hollow Microspheres of Clarithromycin As A Gastroretentive Drug Delivery System Using Eudragit Polymers, International Journal of Pharma And Bio Sciences, 2(3); 2011:344-358.

35. Wen-Chuan Hsieh, Chih-Pong Chang, Ying-Lin Gao, Controlled release properties of Chitosan encapsulated volatile Citronella Oil microcapsules by thermal treatments, Colloids and Surfaces B: Biointerfaces 53; 2006:209–214.

36. Jaina SK, Calcium silicate based microspheres of repaglinide for gastroretentive floating drug delivery: Preparation and in vitro characterization, Journal of Controlled Release 107; 2005:300– 309.

37. P.N. Ezhilarasi , D. Indrani , B.S. Jena , C. Anandharama krishnan, Freeze drying technique for microencapsulation of Garcinia fruit extract and its effect on bread quality, Journal of Food Engineering, 2013.

38. Pao-Chu Wua, Yaw-Bin Huanga, Jui-Sheng Changa, Ming-Jun Tsaib, Yi-Hung Tsai, Design and evaluation of sustained release microspheres of potassium chloride prepared by Eudragit, European Journal of Pharmaceutical Sciences 19; 2003:115–122.

39. Banerjee P et al. Fabrication and Development of Pectin Microsphere of Metformin Hydrochloride, International Scholarly Research Network, 2012, 1-7.

40. Jian You, Fu-de Cui, Xu Han, Yong-sheng Wang, Lei Yang, Ying-wei Yu, Qing-po Li, Study of the preparation of sustained-release microspheres containing zedoary turmeric oil by the emulsion–solvent-diffusion method and evaluation of the self-emulsification and bioavailability of the oil, Colloids and Surfaces B: Biointerfaces 48; 2006:35–41.

41. Prasanth V.V et al. Microspheres - An Overview, International Journal of Research in Pharmaceutical and Biomedical Sciences, 2(2); 2011:332-338.

Received on 25.06.2013 Modified on 02.07.2013

Research J. Pharm. and Tech. 6(9): September 2013; Page 954-961