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 and/or enhance its shelf life².

In a relatively simplistic form, a microcapsule is a small sphere with a uniform wall around it. The material inside the microcapsule is referred to as the core, internal phase or fills.

Most microcapsules have diameters between a few micrometers and a few millimeters.

Fig.2:-Types of Microcapsules³.

Many microcapsules however bear little resemblance to these simple spheres. The core maybe a crystal, a jagged absorbent particle, an emulsion, suspension of solid, or a suspension of smaller microcapsules.

2. History:

The first research leading to development of the micro encapsulation procedure for pharmacist was published by Bungenburg de Jong and Kass in 1931 and dealt with preparation gelatin .Spheres and use of gelatin coacervation process for coating in the late 1930s and 1940s was developed by Green and co-workers of the National Cash Register Co, Dayton, Ohio. He developed the gelatin coacervation process which eventually leads to several patents for carbonless carbon paper⁴.

3. Reasons for Encapsulation:⁵

1) Environmental protection.

2) Reduction of gastric irritation.

3) Liquid to solid conversion.

4) For odour masking

5) Sustained release of medicaments.

6) Taste masking.

The reasons for micro-encapsulation 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. A range of materials are suited for use as the capsule material: lipids, wax crystal starch modified starch cellulose phospholipids and other polymers^.

Enteric coating is applied to localized core release in the small intestine rather than the stomach. These products usually consist of large number of microcapsules having variable release rate because of composition or amount of coating applied, filled into outer hard gelatin capsule shells .Upon ingestion outer shape quickly disintegrate in stomach to liberate up to 3000micro capsules which spread over G.I track, thus insuring more reproducible drug absorption with less local irritation than occurs with many no disintegrating tablet design for sustain release⁵.

4. Properties of Microcapsules⁶.

4.1: Solation of active ingredient:

Isolation of a compound decreases toxicity, irritancy, potential smell.

4.2: Protection:

Sensitive compounds can be isolated from outside and be protected from moisture contamination damage change, for example by UV light evaporation of volatile components reaction with other materials, like oxidation, yeast activity inhibition by spice oleoresins, etc⁶.

4.3: Presentation under solid or liquid form

• Dried microcapsules present a liquid compound as a stable powder.

• Slurry of microcapsules is equivalent to a stable water/oil emulsion, free of surfactants and co-solvents.

• Substances, which are not soluble in water, like some natural food colorants, can be made water soluble by Microencapsulation.

• Microencapsulation allows mixing of incompatible compounds.

4.4: Visual effect

• Big sizes colored capsules (>0.5 μm) offers visual and attractive effects in cosmetic and detergent formulations.

• Capsules may also contain active ingredients such perfumes, vitamins, or essential oils⁶.

4.5: Release of core substance

• Microencapsulation allows immediate or progressive release of the core substances at the right time and at the right place.

• The core materials can be released, usually either by crushing of the shell material under pressure, by heat, or by slow diffusion of the core materials through the shell wall.

4.6: Immediate or Target Release

• Breakage or shear releases all of the core materials at once. This method is used for pressure-sensitive copy paper, adhesives, perfume printing, shampoo.

• Heat release of wax or fat coated substances

• Release by solution of the shell material in a solvent.

4.7: Controlled Release

Releasing by diffusion through the shell wall makes it possible to control the speed at which the core materials are released; this method is used for agricultural chemicals, medicines, flavors. The factors that control how the core materials are released from microcapsules are as follows:

1. Ratio of core materials to shell materials

2. Components and properties of the shell materials (permeability, mechanical strength, surface topography, etc.)

3. Size of the microcapsules⁶.

5. Various Excipients⁷.

5.1: Coating Material

Water-soluble material Water Insoluble Material

Gelatin Ethyl cellulose

Gum Arabic Polyethylene

Starch Polymethacrilate

PVP Polyamide

Carboxy methyl cellulose Poly lactide coglycolide

Hydroxy ethyl cellulose

Arabinogalactan

Polyvinyl alcohol

5.2: Enteric Film Former or Enteric Coating Material⁷

Shellac

Cellulose Acetate Phthalate

Polyvinyl Acetate Phthalate

Hydroxy propyl methyl cellulose

5.3: Other Excipients⁷

Solvents

Water

Methanol

Ethanol

N-propanol

Acetone

Ethyl acetate

Chlorform

Ethyl ether

Carbon tetrachloride

N-hexan

6. Various Types Of Technology^8,9,10.

Many different procedures have been and are being developed for encapsulation processes based on supercritical fluids. In most of these procedures particle formation and encapsulation are combined in a single step. Supercritical fluids are especially suitable for particle formation, as they display a large change in density near the critical point which enables their solvating power to be carefully controlled by small changes in temperature or pressure.

6.1: Rapid Expansion of Supercritical Solutions (RESS)

Processing is used to prepare microspheres. Microencapsulation takes place when a pressurized supercritical solvent containing the shell material and the active ingredient is released through a small nozzle; the abrupt pressure drop causes the desolvation of the shell material and the formation of a coating layer around the active ingredient. A prerequisite for this technology is that the compounds effectively dissolve in the supercritical fluid, which limits its application.

In some cases (RESS-N technology), a non-solvent like a low molecular weight alcohol is added to facilitate the dissolution of the shell material in the supercritical fluid⁸.

Micro-sphere formation and encapsulation by the Rapid Expansion of Supercritical Solution (RESS) technique

6.2: Gas Anti-Solvent method:

Alternatively, a supercritical fluid is used as an anti-solvent that causes precipitation of a dissolved substrate from a liquid solvent. This approach, called the SAS (Supercritical fluid Anti-Solvent) or GAS (Gas Anti-Solvent) method, results in a pronounced volume expansion compare to the RESS, leading to super-saturation and then precipitation of the solutes^10.

The SAS is possible only if the liquid solvent is completely miscible with the supercritical fluid and if the solute is insoluble in this mixture. For these reasons, SAS is not applicable to the precipitation of water soluble compounds, because of the very low solubility of water in scCO2 at appropriate process conditions. This technique and variations thereof have led to the formation of (sub) micron particles.

6.3: Fluidized Bed Techniques:

In this case the separation of the particles prior to encapsulation is operated in a gas stream (air is general).Then once the fluidization is optimum (individual repartition of the particles), the molten coating material is applied in very tiny droplets which created over time a protecting shell.

The nozzle atomizing the matrix can be applied either at the bottom (bottom spray process) or at the top (Top spray process) of the fluidized particles.

For the Bottom spray the use of the Wurster column (a conical partition chamber inside the fluidized chamber) forces the particles to come close to the nozzle so that they will receive equal amount of coating material. But since it does slow down the process, much industrial work in a bottom spray process without Wurster column. A an intermediary solution, the spouted bed system, by devices at the bottom to guide the fluidizing gas stream and a special geometry of the process chamber, the particles are forced to come close to the atomizing nozzle.

In the top spry process, as you can see in the picture above, the particles also are suspended in gas stream, but the shape of the vessel is designed for an optimal circulation of all particle streams very close to the nozzle.

6.4: Extrusion Technology:

Was initially applied in the plastics processing area and after years of development and application, it has become a well-elaborated tool with technical solutions available for other fields like the pharmaceutical industry (for the production of controlled release formulations). The basic idea behind encapsulation using extrusion is to create a molten mass in which the active agents (either liquids or solids), are dispersed or dissolved. Upon cooling, this mass will solidify, thereby entrapping the active components.

Extruders are thermo-mechanical mixers that consist of one or more screws in a barrel. Transport of material within the extruder takes place by the rotational, and sometimes also oscillating, movement of the screw(s). The extruder barrel may be heated, or sometimes cooled. In the context of encapsulation, extrusion can be defined as a processing technique in which melting of the matrix polymers, mixing of components, and shaping of these mixtures are combined to yield a product. Generally, extruders consist of at least one rotating screw inside a barrel. The barrel is often divided into sections to allow for the section-controlled variation in temperature. Connected to the end of the barrel is a “pre die” and the “die head” which latter determines the shape of the final product. Most commercial extruders have a modular design with the option to use a range of screw elements. This allows the process conditions to meet particular requirements in terms of amount and type of shear.

Processes for the production of spherical and mono-disperse beads are of major interest to different industries, e.g. the pharmaceutical, chemical and food industries or in biotechnology. For such bead generation we will describe here 2 interesting technologies based on jet break-up principle:

6.5: The vibration technology¹⁰

This technology is based on an ancient principle (Lord Rayleigh, in the late 19th century) which shown that a laminar liquid jet breaks up into equally sized droplets by a superimposed vibration. The parameters are the frequency, the velocity of the jet and the nozzle diameter¹⁰.

6.6: The jet-cutter technology^10,11,12.

The Jet-Cutter is a simple technology for bead production that meets the requirement of producing mono-disperse beads originating from low up to high viscous fluids with a high throughput

7. Other Techniques to Manufacture the Microcapsules^13,14.

1. Air suspension.

2. Co-acervation phase separation

· Non aqueous vehicle.

· Aqueous vehicle.

· Formation of three immiscible chemical phases.

· Deposition of coating on core material.

· Regidisition of coating.

3. Solvent evaporation.

4. Spray Drying and Spray congealing.

5. Multi-orifice Centrifugal process.

6. Polymerization

· For biodegradable microcapsules

· For non biodegradable microcapsules and nanoparticles.

7. Interfacial polycondensation.

8. Ion-exchange resin.

9. Miscellaneous others methods of encapsulation and entrapment.

· Physical methods

· Dip coating

· In situ polymerization

· Liposomes

· Molecular scale Entrapment¹².

7.1: Physical Methods:

7.1.1: Coacervation-Phase Separation:^12,13^.

The general outline of the process of three steps to carried out under continuous agitation:

1) Formation of three immiscible chemical phases.

2) Deposition of coating.

3) Rigidization of the coating.

Complex coacervation is the separation of an aqueous polymeric solution into two miscible liquid phases: a dense coacervate phase and a dilute equilibrium phase. The dense coacervate phase wraps as a uniform layer around suspended core materials. Complex coacervation can result spontaneously upon mixing of oppositely charged polyelectrolytes in aqueous media. The charges must be large enough to induce interaction, but not too large to cause precipitation.

Complex coacervation parameters are the pH, the ionic strength, the temperature, the molecular weight and the concentration.

Complex coacervation occurs with the neutralization of two oppositely charged polymers. The core material such as an oily phase is dispersed in an aqueous solution of the two polymers. A change is made in the aqueous phase (pH) to induce the formation of a polymer rich phase that becomes the wall material. The coacervates are usually stabilized by thermal treatment, cross linking or desolvation techniques¹⁴.

7.1.2: Interfacial Polycondensation:

Interfacial polycondensation involves the reaction of the various monomers at the interface between two immiscible liquid phases to form a polymer that encapsulates the disperse phase. Usually two reactive monomers are employed, one dissolved in the aqueous disperse containing a solution or dispersion of the core material and the other dissolved after the emulsification steps in the non aqueous phase.

The W/O emulsion formed requires the addition of the emulgent as stabilizers. They diffuse together and rapidly polymerizes at the inter phase between the phase to form a thin coating and the byproduct of the reaction is neutralized by adding material such as an alkaline buffers. The degree of polymerization can be controlled by the reactivity of the monomer chosen, their concentration, and the composition of either phase vehicle and by the temperature of the system .Variation in the particle size of the disperse phase controls the particle size of product. The reaction between the monomers is quenched by deposition of monomer, which is frequently accomplished by adding excess continuous phase vehicle to the emulsion¹⁵.

7.1.3: 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.

7.1.4: Air-Suspension Coati: Air-Suspension Coating ⁸:

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.

7.2: Chemical Methods:

7.2.1: Interfacial Polymerization:^16,17^.

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.

7.2.2: Ion-Exchange Resins:

Ion-Exchange resins contain ionizable groups attached on to an insoluble cross-linked synthetic polymers and can exchange these groups for ions present in the solution with which they are in contact. The most frequently employed polymeric network used is a copolymer of styrene and divinyl benzene that may be produced by a suspension polymerization process in aspherical bed form. The insoluble ion-exchange resins may be supplied in the case of cation exchangers as sodium, potassium or ammonium salts and of anion exchanger usually as chloride. The corresponding acids or base and may be base of hydroxyl form may be regenerated by treatment with acid or base and may be reacted with suitable cationic and anionic drugs for production of sustained release or other type products. The strength and permeability of the final resins is influenced by the degree of cross linking produced by the divinyl content which is varies between 2 and 12% of the copolymers. Weak cationic exchange resins have pKa value of about 6, so that, at pH4 or above their exchange capacity tends to increase. And string cationic resins have pKa value of 1 to 2and so are normally highly dissociated at all PHS encountered in GIT^18-20.

7.2.3: 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 0.2–75 µm (0.0079–2.95 mils). The coating is uniform, even over sharp projections.

7.2.4: Matrix polymerization:²⁰^.

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.

8. Release Methods and Patterns:^21,22^.

Even when the aim of a microencapsulation application is the isolation of the core from its surrounding, the wall must be ruptured at the time of use. Many walls are ruptured easily by pressure or shear stress, as in the case of breaking dye particles during writing to form a copy. Capsule contents may be released by melting the wall, or dissolving it under particular conditions, as in the case of an enteric drug coating.In other systems, the wall is broken by solvent action, enzyme attack, chemical reaction, hydrolysis, or slow disintegration.

Microencapsulation can be used to slow the release of a drug into the body. This may permit one controlled release dose to substitute for several doses of non-encapsulated drug and also may decrease toxic side effects for some drugs by preventing high initial concentrations in the blood. There is usually a certain desired release pattern. In some cases, it is zero-order, i.e. the release rate is constant. In this case, the microcapsules deliver a fixed amount of drug per minute or hour during the period of their effectiveness. This can occur as long as a solid reservoir or dissolving drug is maintained in the microcapsule^23,.

A more typical release pattern is first-order in which the rate decreases exponentially with time until the drug source is exhausted. In this situation, a fixed amount of drug is in solution inside the microcapsule. The concentration difference between the inside and the outside of the capsule decreases continually as the drug diffuses²².

9. Factors Influencing Encapsulation Efficiency:^24,25

The encapsulation efficiency of the micro particle or microcapsule or micro sphere will be affected by different parameters.

1) Solubility of polymer in the organic solvent.

2) Concentration of the polymer.

3) Ratio of dispersed phase to continuous phase (DP/CP ratio).

4) Rate of solvent removal.

5) Interaction between drug and polymer.

6) Solubility of drug in continuous phase.

10. Applications of Micro encapsulation:^26,27

There are almost limitless applications for microencapsulated material. Microencapsulated materials are utilized in agriculture, pharmaceuticals, foods, cosmetics and fragrances, textiles, paper, paints, coatings and adhesives, printing applications, and many other industries. Historically, carbonless copy paper was the first marketable product to employ microcapsules. A coating of microencapsulated colorless ink is applied to the top sheet of paper, and a developer is applied to the subsequent sheet. When pressure is applied by writing, the capsules break and the ink reacts with the developer to produce the dark color of the copy. Today's textile industry makes use of microencapsulated materials to enhance the properties of finished goods. One application increasingly utilized is the incorporation of microencapsulated phase change materials (PCMs). Phase change materials absorb and release heat in response to changes in environmental temperatures. When temperatures rise, the phase change material melts, absorbing excess heat, and feels cool. Conversely, as temperatures fall, the PCM releases heat as it solidifies, and feels warm. This property of microencapsulated phase change materials can be harnessed to increase the comfort level for users of sports equipment, military gear, bedding, clothing, building materials, and many other consumer products²⁴.

Microencapsulated PCMs have even been used in NASA-patented thermal protection systems for spacecraft. Pesticides are encapsulated to be released over time, allowing farmers to apply the pesticides less often rather than requiring very highly concentrated and perhaps toxic initial applications followed by repeated applications to combat the loss of efficacy due to leaching, evaporation, and degradation. Protecting the pesticides from full exposure to the elements lessens the risk to the environment and those that might be exposed to the chemicals and provides a more efficient strategy to pest control.

Ingredients in foods are encapsulated for several reasons. Most flavorings are volatile; therefore encapsulation of these components extends the shelf-life of products by retaining within the food flavors 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. Alternatively, flavors are sometimes encapsulated to last longer, as in chewing gum. The amount of encapsulated flavoring required is substantially less than liquid flavoring, as liquid flavoring is lost and not recovered during chewing. Flavorings that are comprised of two reactive components that, when encapsulated individually, may be added to the finished product separately so that they do not react and lose flavor potential prematurely. Some flavorings must also be protected from oxidation or other reactions caused by exposure to light ²⁶.

Many varieties of both oral and injected pharmaceutical formulations are microencapsulated to release over longer periods of time or at certain locations in the body. Aspirin, for example, can cause peptic ulcers and bleeding if doses are introduced all at once. Therefore aspirin tablets are often produced by compressing quantities of microcapsules that will gradually release the aspirin through their shells, decreasing risk of stomach damage.

11. REFERENCES:

1. Leon Lachman, Herbert A.Lieberman, Joseph L.Kanig.The Theory and practice of Industrial pharmacy .3^rd ed: pp.412-426.

2. http://www.gate2tech.com/article.php3?id_article=25

3. http://images.google.co.in?images?q=microencapsulationandhl=enandoe=UTF-8andum=1andie=UTF-8andtab=wi

4. Alfonso R.Gennaro, Remington. The science and practice of pharmacy, 20^th ed: pp.891-893.

5. http://www.wikipedia.org/microencapsulation #Reasons for encapsulation.

6. Amiet Charpentierc, Gadille P. Benoit J.P Paper:Rhizobacteria Microencapsulation: Properties of micro particles obtained by spray drying, pp.9-15.

7. N.K.Jain, Pharmaceutical drug development, 1^st Ed: pp.125-135.

8. Patrick B.Deasy, Micro encapsulation and related drug process Volume-20;pp:61-89;119;145;153;161-177;241-245;265-286 and Simon Benita, Micro encapsulation method and industrial applications; second edition by vol.-158;pp. 230-231;233;235-238.

9. Kalb,P.D., and P.R. Lageraaen, “Polyethylene Encapsulation Full-Scale Technology Demonstration,” BNL-52478, Brookhavaen National Laboratory, Upton, NY, 1995.

10. M.W.Ranney, Microencapsulation Technology, Noyes Development Corporation park Ridge, 1969, pp.275

11. Ghulam Murtaza Mahmood Ahamd.Pak,J Paper:-A Comparative study of various Microencapsulation techniques by Pharma sci.Vol.22.3 July-2009, pp291-300.

12. Ghosh S.K, Paper-Functional Coating and Microencapsulation: A General perspective: pp12-23.

13. http://www.swri.org/4org/d01/microenc/microen/atomization.htm

14. http://www.bnl.gov/des/ertd/TechDevelApp/kineticreport.asp#2.1

15. Patel,B.R., P.R. Lageraaen, and p.d. Kalb, “Reviev of Potential processing techniques for the Encapsulation of Wastes I Thermoplastic Polymers,” BNL-62200,Brookhaven National Laboratory, Upton, NY,August1995.

16. Journal of control release vol-104, Issue-3, 2/June/2005, Page number 447-460.

17. The Internet Journal of Nanotechnology Issue1937-8262 ISPUB.com. Microencapsulation Techniques, factors Influencing Encapsulation Efficiency A review file: pp09-19 Published online.

18. http://www.micap.biz

19. John Franjiory and Niraj Vasishtha, Journal:-Technology Today Published By Southwest Research Institute: The Art and Science Of Microencapsulation,pp12-19.

20. http://globalspec.com.

21. Paper: Cell Culture and Tissue Engineering Progress technology in Microencapsulation method- Jean-Michel Raband_2009_Wiley Inter Sci.Reviced-25 Feb-2009.

22. http://www.bayareaIP.com

23. http://www.sono-tek.com/medical/subcategory/microencapsulation

24. Journal of Macromolecular Bioscience Volume-7, Issue-6, pp: 767-783 Published online 31 May 2007.

25. http://www.sandia.gov/news/resources/releases/2008/microenc.htm.

26. http://www.pharmainfo.net/pharma-student-magazine/lipid-based-drug-delivery-liphophilic-drugs

27. http://www.rtdodge.com/products2.html.

Received on 10.04.2010

Accepted on 13.05.2010

Research Journal of Pharmaceutical Dosage Forms and Technology. 2(4): July-August 2010, 270-276

7.1: Physical Methods:

7.1.3: 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.

7.1.4: Air-Suspension Coati: Air-Suspension Coating 8:

8. Release Methods and Patterns:21,22.

7.1.4: Air-Suspension Coati: Air-Suspension Coating ⁸:

8. Release Methods and Patterns:^21,22^.