Microcapsules can be classified into three basic categories according to their morphology as mono-cored, poly-cored, and matrix types, as shown in Figure.⁴

Fig. Classification of microparticles from their morphology

ENCAPSULATED PHASE CHANGE MATERIALS

Encapsulated phase change materials (PCM’s) consist of an encapsulated substance with a high heat of fusion which absorbs and releases thermal energy in order to maintain a regulated temperature within a product (such as clothing, upholstery, packaging and building materials). They come in either microcapsule or macrocapsule form.⁵

Micro PCM's

Macro PCM's

►One frequently used microencapsulation process involves stirring an aqueous core and an organic solvent containing a dissolved polymer shell material into an emulsion.⁶

►Cell encapsulation in biocompatible and semipermeable polymeric membranes is an effective method for immunoprotection, regardless of the type of recipient⁷. For in vitro study of this filled microencapsulated cells are used.

Microencapsulation technologies have advanced significantly during the past few decades, leading to many successful commercial products. Since the early promise of sustained protein delivery [8], research on protein microencapsulation has been increased exponentially Microencapsulation of protein drugs, how- ever, still remains one of the most challenging subjects in the controlled drug delivery area. Due to the high sensitivity of proteins to harsh conditions that can occur during the microencapsulation process, maintaining the functional integrity of the encapsulated protein drugs is not easy^9-13. Recently, a new way of microencapsulation that utilized multiple concentric nozzles to generate double-walled microspheres was developed adding flexibility in combined use of the different polymers.¹⁴ The hydrophobic interaction between the protein and polymers has been minimized by encapsulating proteins within hydrophilic excipients prior to polymeric encapsulation.^15,16

Biodegradable polymer particles (e.g., microspheres, microcapsules, and nanoparticles) are highly useful because they can be administered to a variety of locations in vivo through a syringe needle^17,18. A variety of drugs, regardless of their molecular weights and water solubility, can be loaded into the biodegradable microparticles using different manufacturing techniques^19-23.

MICROENCAPSULATION AS AN ART:

Microencapsulation is like the work of a clothing designer. He selects the pattern, cuts the cloth, and sews the garment in due consideration of the desires and age of his customer, plus the locale and climate where the garment is to be worn. By analogy, in microencapsulation, capsules are designed and prepared to meet all the requirements in due consideration of the properties of the core material, intended use of the product, and the environment of storage.²⁴

FUNDAMENTAL CONSIDERATION:

Core material: 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 material.

Coating material: Different type of coating materials are used in Microencapsulation.

Water soluble resins: Gelatin, Gum Arabic, PVP, CMC, Hydroxy methyl cellulose, methyl cellulose, poly vinyl alcohol.

Water insoluble resins: Ethyl cellulose, polyethylene, polymethacrylate, nylon, cellulose nitrate, silicones.

Waxes and lipids: Paraffin, carnauba, spermaceti, beeswax, stearic acid Searyl alcohol, Glyceryl stearates.

Enteric resins: Shellac, cellulose acetate phthalate, Zein ¹

TECHNIQUES OF MICROENCAPSULATION : A number of microencapsulation methods have been developed to such a level that one can choose a proper method depending upon the physicochemical properties of the drug and the polymer to be used.²⁵

Microencapsulation Process	Applicable core material	Approximate particle size (Micro meter)
Air suspension	Solids	35-5000
Coacervation phase separation	Solids and liquid	2-5000
Multiorifice centrifugal	Solids and liquid	1-5000
Pan coating	Solids	600-5000
Solvent evaporation	Solids and liquids	5-5000
Spray drying and congealing	Solids and liquids	600

TECHNIQUES FOR LIPOSOME MICROENCAPSULATION:

The lipid-aqueous system needs to meet two major requirements for the liposome microencapsulation to occur. First, the system needs have a negative free energy, and second, it needs to overcome the energy barrier which is necessary for the formation of the bilayer. Three methods of liposome preparation are here described:

A. Microfluidization: Microencapsulation by this method is obtained through the dynamic interaction of two pressurized aqueous-lipid fluids that create a large momentum and flow turbulence that allows the system to overcome the energy barrier to microcapsule formation. The pressure applied in air-driven microfluidizers can be as high as 10,000 psi (Kim and Baianu, 1993). The ultra-high velocities reached by this technique allow the creation of small liposomes (< ~0.3μm) with high capture efficiency (Mayhew and Lazo 1984). This system is useful because of its capability to produce very large amounts of liposomes with adjusted size in a continuous process.

B. Ultrasonication: The ultrasound absorption is employed to overcome the energy barrier. The sonication of the lipid emulsion can be carried out by two different approaches. The first one is through the use 15 of a sonication probe placed directly into the suspension of liposomes. The second method is slower than the first one and employs a sonication bath, such as a sealed container filled with Nitrogen or Argon gas. Both methods have been extensively applied for the formation of SUV’s; however, the use of a sonication probe has been found to cause contamination of the liposomes

(Taylor 1983).

C. Reverse phase evaporation: Reverse phase evaporation is used for the preparation of LUV’s (Szoka and Papahadjopoulos 1978) and it is based upon the extraction of a nonpolar solvent from an aqueous–nonpolar inverted micelle by rotatory evaporation under vacuum. This withdrawal of the nonpolar phase changes the intermediate gel-like phase of the micelle into uni-lamellar and oligo-lamellar vesicles (Kim and Bainu 1993). The advantage of this technique is the uniformity of the vesicles formed (from about 0.2 to1.0 μm) as well as their high encapsulation efficiency. On the other hand, the exposure of the components to organic solvents and sonication is likely to result in protein denaturation (Szoka and Papahadjopoulos 1980).²⁶

Physical Methods of Encapsulation: (1) Spray drying (2) Spray chilling (3) Fluid bed coating (4) Stationary nozzle coextrusion (5) Centrifugal head coextrusion (6) Submerged nozzle coextrusion (7) Pan coating.

Chemical Methods of Encapsulation: (1) Phase separation (2) Solvent evaporation (3) Solvent extraction (4) Interfacial polymerization (5) Simple and complex coacervation (6) In-situ polymerization (7) Liposome technology (8) Nanoencapsulation

Unique Release Mechanisms:

· Controlled, sustained, delayed, targeted release

· Enteric, thermal, pressure, osmotic, pH-induced, pulsatile release

· Biodegradable or salt-induced release

· Oral, inject able, pulmonary, intranasal, implantable drug delivery¹

PHYSICAL METHODS:

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. With respect to the 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 beds. The particles are tumbled in a pan or other device while the coating material is applied slowly. The standard coating pan system consists of a circular metal pan mounted somewhat angularly on a stand. The pan is 8 to 60 inches in diameter and is rotated on its horizontal axis by a motor. Heated air is directly into the pan and onto the tablet bed surface, and is exhausted by means of ducts positioned through the front of the pan. Coating solutions are applied to the tablets by ladling or spraying the material onto the rotating tablet bed. Se of atomizing systems to spray the liquid coating material onto the tablets produces faster, more even distribution of the solution or suspensions. Spraying can significantly reduce drying time between solution applications in sugar coating processes and allows for continuous application of the solution in film coating.¹

MULTIORIFICE CENTRIFUGAL PROCESS:

Introduction: The Southwest Research Institute (SWRI) has developed a mechanical process for producing microcapsule that utilizes centrifugal forces to hurl a core material particle through an enveloping microencapsulation membrane, thereby effecting mechanical microencapsulation.The apparatus, illustrated cross sectionally in figure, depicts a rotating cylinder, 1, a major and essential portion of the device. Located within the cylinder are three circumferential grooves, 2, 3, 4. Countersunk in the intermediate groove, 3 are a plurality of orifice space closely and circumferentially around the cylinder. The upper and lower grooves, also located circumferentially around the cylinder, carry the coating material in molten or solution form, via tube, 5, to the respective grooves. The ridges of the coating material grooves, 2 and 4 , serves as a weir over which the coating material overflows when the volume of the upper and lower grooves is exceeded by the volume of material pumped into the system. The coating material, 6, under centrifugal force imparted by the cylinder rotation, flows outward along the side of the immediate groove into the countersunk portion and forms a film across the orifice. A counter rotating disk, 7, mounted within the cylinder, atomizes or disperses the core material fed through the centrally located inlet, 8. The rotating disk flings the particulate core material (liquid droplets or solid particles) toward the orifices. The core material arrives at the orifices and encounters the coating material membrane. The impact and centrifugal force, generated by the rotating cylinder, hurls the core material through the enveloping coating membrane, 9, which is immediately regenerated by the continually overflowing coating material. The embryonic microcapsule, upon leaving the orifices, are hardened, congealed or voided of coating solution by a variety of means.¹

Application: The efficiency and cost effective encapsulation of a wide range of components by extrusion technology were clearly in favor of the development of such flexible and continuous process. As both hydrophilic and hydrophobic components can be encapsulated either in hydrophilic or hydrophobic matrix materials, melt-extrusion is able to encapsulate; flavors, fragrances, essential oil, agrochemicals, nutraceuticals, pharmaceutically active compounds (e.g. for oral dosage forms, implants, topical films), living cells

COMPLEX COACERVATION TECHNIQUE:

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 polyelectrolyte in aqueous media. The charges must be large enough to induce interaction, but not too large to cause precipitation.

Effect of surfactant: The presence of an anionic and cationic surfactant is known to increase the microcapsule yield dramatically.²⁷

Basically complex coacervation process consists of three steps:

[1] Formation of an oil-in-water emulsion or formation of three immiscible chemical phases.

[2] Formation of the coating or Deposition of the coating.

[3] Stabilization of the coating or rigidization of the coating.¹

The microcapsules are usually collected by filtration or centrifugation, washed with an appropriate solvent and subsequently dried (air-dried or by standard techniques such as by fluid bed or spray drying).

Procedure: This method involves phase separation of a polymer solution by adding an organic nonsolvent^28-30. Drugs are first dispersed or dissolved in a polymer solution. To this mixture solution is added an organic nonsolvent (e.g., silicon oil) under continuous stirring, by which the polymer solvent is gradually extracted and soft coacervate droplets containing the drug are generated. The rate of adding nonsolvent affects the extraction rate of the solvent, the size of microparticles and encapsulation efficiency of the drug. The commonly used nonsolvents include silicone oil, vegetable oil, light liquid paraffin, and low-molecular-weight polybutadiene. The coacervate phase is then hardened by exposing it into an excess amount of another nonsolvent such as hexane, heptane, and diethyl ether. The characteristics of the final microspheres are determined by the molecular weight of the polymer, viscosity of the nonsolvent, and polymer concentration^31,32. The main disadvantage of this method is a high possibility of forming large aggregates. Extremely sticky coacervate droplets frequently adhere to each other before complete phase separation.

Figure. Formation of mononuclear reservoir-type microcapsules by interfacial phase separation. Two different liquid droplets produced from ink-jet nozzles collide each other in the air. The solvent exchange occurs at the interface between two liquids to form a polymer layer on the aqueous core. The formed microcapsules are collected in the water bath.

EMULSION STABILISATION:

Introduction: Preparation of protein- and polysaccharide-based microcapsules and microspheres using the “emulsion crosslinking” or “emulsion stabilization” technology is very frequent. This method can be used for the encapsulation of soluble or insoluble liquids, or solid agents to be released by diffusion, erosion or dissolution.

Technology: Emulsion stabilization is a technique based on single or double emulsions. Since many biopolymers are generally water-soluble, two systems can be distinguished when biopolymers are used as wall material.

1. Hydrophilic active ingredients:

Single water-in-oil (W/O)-emulsions are employed if the active ingredient is water-soluble. In this case an aqueous biopolymer solution containing the active ingredient is emulsified in a hydrophobic phase like vegetable oil or organic solvent. When the desired droplet size is obtained, the matrix material is stabilized by cross linking. Then, the oil phase is removed by washing with solvents like hexane and the particles are isolated. The particles can either be dried to obtain a powder, or used as slurry.

2. Hydrophobic active ingredients: Double oil-water-oil (O/W/O)-emulsions can be used if the active ingredient is hydrophobic. The active ingredient is first added to an oil phase. This oil phase is then emulsified in the aqueous biopolymer phase to form an O/W-emulsion. Then the O/W-emulsion is added to a hydrophobic phase to form the double O/W/O-emulsion. Common challenge with emulsion stabilization for hydrophobic ingredients is retention of the core; often losses occur during the encapsulation process. The main advantages of this technology are the flexibility in controlling the degree of stabilization and the small particle size that can be obtained. Disadvantages include the costs and effort related to removal of oil phase and the loss of encapsulant during processing. Moreover, Spray Drying of emulsions is another technology for production of microcapsules with emulsions as a starting point. This technology will be described in a separate technology (spray drying).

Application:

• Drug delivery systems

• Encapsulation of fragrances for laundry applications

• Encapsulation of ingredients for food applications and Encapsulation of pesticides⁸

SPRAY DRYING AND SPRAY CONGEALING:

Spray drying and spray congealing process 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 of the coating is effected. 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 Nonsolvent. Removal of the Nonsolvent or solvent from the coated product is then accomplished by sorption, extraction, or evaporation techniques. Microencapsulation by spray drying is conducted by dispersing a core material in a coating solution. In which the core material is insoluble, and then by atomizing the mixture into the 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. The equipment components of a standard spray dryer include an air heater, atomizer, main spray chamber, blower or fan, cyclone and product collector. The process produces microencapsules approaching a spherical structure in the size range of 5 to 600 microns. Characteristically, spray drying yields products of low bulk density, owing to the porous nature of the coated particle. 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 spray drying, except that the core material is dispersed in a coating material melt rather than a coating solution. Coating solidification is accomplished by spraying the hot mixture into the 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 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 other variables.¹

AIR SUSPENSION COATING: 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.

FIG-IX: SPRAY DRYING

FIG-X: SPRAY CHILLING

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. It is also known as WURSTER process, consists of the dispersing of solid, particulate core materials in a supporting air stream and the spray-coating of the air suspended particles. In coating chamber, particles are suspended on an upward moving air stream as indicated in diagram. Fluidization (or fluidization) is a process similar to liquefaction whereby a granular material is converted from a static solid-like state to a dynamic fluid-like state. This process occurs when a fluid (liquid or gas) is passed up through the granular material. When a gas flow is introduced through the bottom of a bed of solid particles, it will move upwards through the bed via the empty spaces between the particles. At low gas velocities, aerodynamic drag on each particle is also low, and thus the bed remains in a fixed state. Increasing the velocity, the aerodynamic drag forces will begin to counteract the gravitational forces, causing the bed to expand in volume as the particles move away from each other. Further increasing the velocity, it will reach a critical value at which the upward drag forces will exactly equal the downward gravitational forces, causing the particles to become suspended within the fluid. At this critical value, the bed is said to be fluidized and will exhibit fluidic behavior. By further increasing gas velocity, the bulk density of the bed will continue to decrease, and its fluidization becomes more violent, until the particles no longer form a bed and are “conveyed” upwards by the gas flow. When fluidized, a bed of solid particles will behave as a fluid, like a liquid or gas. Like water in a bucket: the bed will conform to the volume of the chamber, its surface remaining perpendicular to gravity; objects with a lower density than the bed density will float on its surface, bobbing up and down if pushed downwards, while objects with a higher density sink to the bottom of the bed. The design of the chamber and its operating parameters effect a recalculating flow of the particles through the coating 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 of the purpose of microencapsulation, the coating thickness 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 volume temperature of the supporting air stream.

Processing variables that receive consideration for efficient, effective encapsulation by air suspension techniques include the following:

1. Density, surface area, melting point solubility, friability, volatility, crystallinity, and flowability of the core material.

2. Coating material concentration (or melting point if not a solution)

3. Coating material application rate

4. Volume of air required to support and fluidizes the core material

5. Amount of coating material required.

6. Inlet and outlet operating temperatures.

The process has the capability of applying coating in the form of solvent solution, aqueous solution, emulsions, dispersions, or hot melts in equipment ranging in capacities from one pound to 990 pounds. The air suspension technique is applicable to both microencapsulation and macroencapsulation coating process.¹

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.

SUPER CRITICAL FLUID TECHNOLOGY:

Introduction: Microencapsulation using supercritical fluid technology combines a liquid-like density and solvating power with gas-like transport properties (like viscosity, diffusivity). They are applied on a large industrial scale, e.g. for extractions and reactions. For microencapsulation purposes, the mild processing conditions give supercritical fluid technology an important advantage over other methods that include harsh treatments with regard to pH, temperature, or the use of organic solvents. Carbon dioxide is the most widely used supercritical fluid because of its relatively low critical temperature (31 °C) and pressure (74 bars). In particular, its low critical temperature makes it highly suitable for processing heat-sensitive materials. In addition, supercritical CO₂ (scCO₂) is non-toxic, non-flammable, inexpensive, and has GRAS (generally regarded as safe) status. These characteristics enable a broad range of food and non-food applications. Supercritical CO₂ is a non-polar solvent with dissolution properties that are comparable to hexane.

Technology: 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. Here we will describe two distinct approaches for particle formation and encapsulation using supercritical fluids.

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 fluid.

2- 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. 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.

Application : The use of supercritical fluid technology, especially scCO₂, for encapsulation purposes is mainly due to the mild processing condition, allowing microencapsulation of sensitive ingredients for: cosmetics (vitamin, pigments and dyes, nanoparticles...), pharmaceuticals (therapeutics proteins...) food (volatile flavors, vitamins...) , Impregnation of matrix materials with (bio)active ingredients, for development of slow- or controlled- release systems.²

CHEMICAL METHODS:

Interfacial polymerization: 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.

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. The continuous or core material supporting phase is usually a liquid or gas, and therefore the polymerization reaction occurs at a liquid-liquid, liquid-gas, solid-liquid, or solid-gas interface.

Matrix polymerization: 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.

COMPARISON OF DIFFERENT MICROENCAPSULATION TECHNIQUES:

Example: A comparison of different microencapsulation techniques for the production of enteric microparticles from the acrylic polymer Eudragit L100.³³

► Wettability of the spray-dried particles was poor, due to collapsed and irregular morphology, and drug release after 2 hours in acid exceeded 10%.

►Microparticles produced by emulsification/solvent evaporation dispersed well, and despite their small size, provided excellent control of drug release at acidic pH, whilst releasing 100% of prednisolone within 5 minutes at intestinal pH.

►>85% of core pellets produced by extrusion-spheronisation were >500μm in diameter. Coating of 500-710μm pellets was problematic.

APPLICATION OF MICROENCAPSULATION:

Figure-XIV: applications of micro-encapsulation

Microcapsule application: [34]

Purpose	Application
1. Taste masking	Fish oil, salts, alkaloids, clofibrate, sulfa drugs
2. Drug instability to storage	Sensitivity to O_2,H₂O, volatility (Vitamin, aspirin, volatile flavors)
3. Drug instability to formula components	Isolation from excipients, buffer, other drugs
4. Drug instability to Digestive juices	Degradables (proteins, enzymes, esters, erythromycin)
5. Drug instability to Body defenses	Artificial cells (Proteins, peptides, enzymes, charcoal)
6. Isolation from tissues	Irritants, ulcerants (aspirin, KCl)
7. Dry handling (better mixing and flow)	Liquids; soft, sticky solids (oils, flavors, vitamin A, perfumes)
8. Sustained and controlled release	Many drugs and agents [Coating: inert, pH-dependent, degradable, permeable or impermeable to ions and buffer agents]
9. Targeted delivery	Drugs of low therapeutics index or high systemic toxicity (e.g. cytotoxic drugs) in small microcapsule and nanoparticles
10. Exchange reactions	Artificial cells and organs, detoxification
11. Biotechnology	Diagnostic aids (thermography, radioimmunoassay); biosynthesis (insulin, monoclonal antibodies)

REFERENCES:

1. Lachman Leon; “The Theory and Practice of industrial Pharmacy”; Third Indian Edition; Varghese Publishing House; Dadar Bombay;2004; 412-427.

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

3. "http://parts.mit.edu/igem07/index.php/Boston_University/Microencapsulation"

4. Hidekazu Yoshizawa, “Trends in Microencapsulation Research”; Department of Environmental Chemistry and Materials, Faculty of Environmental Science and Technology, Okayama University; KONA No.22 (2004)

5. Michael C. Smith and Mohammed M. Farid, “Areview on microencapsulation techniques for phase change materials”, Department of Chemical and Materials Engineering; the University of Auckland, New Zealand.

6. www.sandia.gov-news-resources-releases-2008-images-microenc1.jpg.files\microenc.htm

7. JIANG Qiang, ZHANG Su-zhan, PENG Jia-ping, WANG Xu-lin, “Preparation and in vitro studies of microencapsulated cells releasing human tissue inhibitor of metalloproteinase-2”, Jiang et al. / J Zhejiang Univ SCI 2005 6B (9):859-864

8. R. Langer, J. Folkman, Polymers for the sustained release of proteins and other macromolecules, Nature 263 (1976) 797–800.

9. S.P. Schwendeman, H.R. Constantino, R.K. Gupta, G.R. Siber, A.M. Klibanov, R. Langer, Stabilization of tetanus and diphtheria toxoids against moisture-induced aggregation, Proc. Natl. Acad. Sci. U. S. A. 92 (1995) 11234–11238.

10. S.P. Schwendeman, Recent advances in the stabilization of proteins encapsulated in injectable PLGA delivery systems, Crit. Rev. Ther. Drug Carr. Syst. 19 (1) (2002) 73–98.

11. M. van de Weert, W.E. Hennink, W. Jiskoot, Protein instability in PLGA microparticles, Pharm. Res. 17 (10) (2000) 1159– 1167.

12. C. Perez, I.J. Castellanos, H.R. Costantino, W. Al-Azzam, K. Griebenow, Recent trends in stabilizing protein structure upon encapsulation and release from bioerodible polymers, J. Pharm. Pharmacol. 54 (3) (2002) 301–313.

13. S.D. Putney, P.A. Burke, Improving protein therapeutics with sustained-release formulations, Nat. Biotechnol. 16 (1998) 153–157.

14. C. Berkland, E. Pollauf, D.W. Pack, K.K. Kim, Uniform double-walled polymer microspheres of controllable shell thickness, J. Control. Release 96 (2004) 101–111.

15. N. Wang, X.S. Wu, A novel approach to stabilization of protein drugs in PLGA microspheres using agarose hydrogel, Int. J. Pharm. 166 (1998) 1– 14.

16. M. Tobio, S.P. Schwendeman, Y. Guo, J. McIver, R. Langer, M.J. Alonso, Improved immunogenicity of a corecoated tetanus toxoid delivery system, Vaccine 18 (2000) 618–622.

17. Jain, R. A. The manufacturing techniques of various drug loaded biodegradable poly (lactide coglycolide) (PLGA) devices. Biomaterials 2000, 21, 2475-2490.

18. Berkland, C.; King, M.; Cox, A.; Kim, K.; Pack, D. W. Precise control of PLG microsphere size provides enhanced control of drug release rate. J. Control. Release 2002, 82, 137-147.

19. Felder Ch, B.; Blanco-Prieto, M. J.; Heizmann, J.; Merkle, H. P.; Gander, B. Ultrasonic atomization and subsequent polymer desolvation for peptide and protein microencapsulation into biodegradable polyesters. J. Microencapsul. 2003, 20, 553-567.

20. Kiyoyama, S.; Shiomori, K.; Kawano, Y.; Hatate, Y. Preparation of microcapsules and control of their morphology. J. Microencapsul. 2003, 20, 497-508.

21. Sinha, V. R.; Trehan, A. Biodegradable microspheres for protein delivery. J. Control. Release 2003, 90, 261-280.

22. Sinha, V. R.; Goyal, V.; Bhinge, J. R.; Mittal, B. R.; Trehan, A. Diagnostic microspheres: an overview. Crit Rev The Drug Carrier Syst 2003, 20, 431-460.

23. Wang, J.; Chua, K. M.; Wang, C. H. Stabilization and encapsulation of human immunoglobulin G into biodegradable microspheres. J. Colloid Interface Sci. 2004, 271, 92-101.

24. John Franjione and Niraj Vasishtha, “The Art and Science of Microencapsulation”, Published in the Summer 1995 issue of Technology Today, published by Southwest Research Institute.

25. Yoon Yeo, Alvin U. Chen, Osman A. Basaranand Kinam Park, “Solvent Exchange Method: A Novel Microencapsulation Technique Using Dual Microdispensers”, Pharmaceutical Research; Springer Netherlands, vol. 21, No. 8, august 2004, 1.

26. I.C. Baianu, P.R. Lozano, V.I. Prisecaru and H.C. Lin, “Novel Techniques and Their Applications to Agricultural Biotechnology, Health Foods and Medical Biotechnology”, University of Illinois at Urbana, ACES College; 13

27. A. Bhattacharyya, J-F.Argillier, “Microencapsulation by complex coacervation – Effect of cationic surfactant”, J. surface sci. tehnol., Volume-21, No. 3-4, pp. 161-168, 2005.

28. Carrasquillo, K. G.; Stanley, A. M.; Aponte-Carro, J. C.; De Jesus, P.; Costantino, H. R.; Bosques, C. J.; Griebenow, K. Non-aqueous encapsulation of excipient-stabilized spray-freeze dried BSA into poly(lactide-co-glycolide) microspheres results in release of native protein. J. Control. Release 2001, 76, 199-208.

29. Mallarde, D.; Boutignon, F.; Moine, F.; Barre, E.; David, S.; Touchet, H.; Ferruti, P.; Deghenghi, R. PLGA-PEG microspheres of teverelix: influence of polymer type on microsphere characteristics and on teverelix in vitro release. Int. J. Pharm. 2003, 261, 69-80.

30. Johansen, P.; Moon, L.; Tamber, H.; Merkle, H. P.; Gander, B.; Sesardic, D. Immunogenicity of single-dose diphtheria vaccines based on PLA/PLGA microspheres in guinea pigs. Vaccine 1999, 18, 209-215.

31. Ruiz, J. P.; Tissier, B.; Benoit, J. P. Microencapsulation of peptide: a study of the phase separation of poly (D, L-lactic acid-co-glycolic acid) copolymers 50/50 by silicone oil. Int. J. Pharm. 1989, 49, 69-77.

32. Ruiz, J. M.; Busnel, J. P.; Benoit, J. P. Influence of average molecular weights of poly(DL-lactic acid-co-glycolic acid) copolymers 50/50 on phase separation and in vitro drug release from microspheres. Pharm. Res. 1990, 7, 928-934.

33. R. Kendall, S. Murdan, A. Basit; “A comparison of different microencapsulation techniques for the production of enteric microparticles from the acrylic polymer Eudragit L100”, Department of Pharmaceutics, The School of Pharmacy

34. Max Donbrow; “Microcapsules and Nanoparticles in Medicine and Pharmacy”; Introduction and overview; chapter 1; page no. 3, 8

Received on 12.09.2010

Accepted on 14.04.2011

Research Journal of Pharmaceutical Dosage Forms and Technology. 3(3): May-June 2011, 75-83

Microencapsulation

Process

Applicable core material

Approximate particle size

(Micro meter)

Air suspension

Solids

35-5000

Coacervation phase separation

Solids and liquid

2-5000

Multiorifice centrifugal

Solids and liquid

1-5000

Pan coating

Solids

600-5000

Solvent evaporation

Solids and liquids

5-5000

Spray drying and congealing

Solids and liquids

600

COMPARISON OF DIFFERENT MICROENCAPSULATION TECHNIQUES:

APPLICATION OF MICROENCAPSULATION:

Figure-XIV: applications of micro-encapsulation