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1 ISSN: X CODEN: IJPTFI Available through Online Review Article IMPORTANCE AND CHARACTERIZATION OF MICROENCAPSULATION TECHNIQUES IN PHARMACEUTICAL DOSAGE FORMS - A REVIEW B.V.Subbaiah*, B.Krishnamoorthy*, M.Muthukumaran. Montessori Siva Sivani Institute of Science & Technology- College of pharmacy, Mylavaram, Vijayawada, Andrapradesh bodepudivenkatasubbaiah@gmail.com Received on Accepted on Abstract Microencapsulated dosage forms represent effective new therapeutic platforms. This special issue will cover the different interests of microencapsulation as a means to control or modify the release of drug substances from drug delivery systems. To overcome the drug stability problem, since clinical efficacies have been reported to be improved by the encapsulation of pharmaceuticals, the bioavailability of drugs, control drug release kinetics, minimizing drug side effects, and taste masking of the drug substances. Microencapsulation is process of enclosing micro sized particles in a polymeric shell. There are different techniques available for the encapsulation of drug entities. Most of the applied techniques of micro-encapsulation are based on modifications of the four basic methods: spray-drying, phase separation (coacervation), gelation and solvent extraction/evaporation. The encapsulation efficiency of the microparticle or microsphere or microcapsule depends upon different factors like concentration of the polymer, solubility of polymer in solvent, rate of solvent removal, solubility of organic solvent in water etc. The present review article provides a different microencapsulation techniques and different factors influencing the encapsulation efficiency of the microencapsulation techniques based on research studies reported. Keywords: Microencapsulation, Encapsulation Efficiency, Coacervation, Coating materials. Introduction An important class of polymer mediated drug delivery systems that are applied for controlled drug delivery is the microcapsules. Microencapsulation provides the means of converting liquids to solids, of altering colloidal and surface properties, of providing environmental protection and controlling release characteristics or availability of coated IJPT Jan-2013 Vol. 4 Issue No Page 2332

2 materials. [1] The recent research has been heavily involved particularly on how the distribution of release controlling parameters among the individual microcapsules of the batch alters the release profile.the development of oral controlled release systems has been a challenge to formulation scientist due to their inability to restrain and localize the system at targeted areas of gastrointestinal tract. Micro particulate drug delivery systems are an interesting and promising option when developing an oral controlled release system. The size range (2 to 2000 µm approximately) distinguishes them from the smaller nanoparticles or nanocapsules. [2] MORPHOLOGY OF MICROCAPSULES The morphology of microcapsules depends mainly on the core material and the deposition process of the shell. 1. Mononuclear: (core-shell) Microcapsules contain the shell around the core. 2. Poly nuclear: Capsules have many cores enclosed within the shell. 3. Matrix encapsulation: In which the core material is distributed homogeneously into the shell material. REASONS FOR ENCAPSULATION 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 properties of a sticky material or isolating a reactive core from chemical attack. [2-3] There are several reasons why substances may be encapsulated [4-5] 1. To protect reactive substances from the environment. 2. To convert liquid active components into a dry solid system. 3. To separate incompatible components for functional reasons. 4. To mask undesired properties of the active components. 5. To protect the immediate environment of the microcapsules from the active Components. APPLICATIONS OF MICROENCAPSULATION The technology has been used widely in the design of controlled release and sustained release dosage forms. [6,7,8] 1. To mask the bitter taste of drugs like Paracetamol, Nitrofurantoin etc. IJPT Jan-2013 Vol. 4 Issue No Page 2333

3 2. To reduce gastric and other gastro intestinal (G.I) tract irritations, For eg., 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, eg. Eprazinone. 4. Hygroscopic properties of core materials may be reduced by microencapsulation eg. Sodium chloride. 5. Carbon tetra chlorides 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. FORMULATING AGENTS FOR MICROENCAPSULATION Preparation of microspheres should satisfy certain criteria, like basic understanding of the general properties of microcapsules, such as the nature of the core and coating materials, the stability and release characteristics of the coated materials and the microencapsulating methods. [9] CORE MATERIAL The core material defined as the specific material to be coated of the core material is varied, as the liquids core can include can be liquid or solid in nature. The composition dispersed and/or dissolved material. The solid core can be a mixture of active constituents, stabilizers, diluents, recipients and release-rate retardants or accelerators. The ability to vary the core material composition provides definite flexibility and utilization of this characteristic often allows effectual design and development of the desired microcapsule properties. [10] Fig.1Shows the Microspheres or microcapsule IJPT Jan-2013 Vol. 4 Issue No Page 2334

4 COATING MATERIALS B.V.Subbaiah* et al. /International Journal Of Pharmacy&Technology The selection of a specific coating material is a lengthy list of candidate materials presents the following questions to be considered by the research. The typical coating properties such as cohesiveness, permeability, moisture sorption, solubility, stability and clarity must be considered in the selection of the proper microcapsule coating material. The selection of a given coating often can be aided by the review of existing literature and by the study of free or cast films, although practical use of free film information often is impeded for the following reasons. [7] Cast or free films prepared by the usual casting techniques yield films that are considerably thicker than those produced by the micro encapsulation of small particles, hence, the results obtained from the cast films may not be extrapolatable to the thin microcapsule coatings. The particular micro encapsulation method employed for the deposition of a given coating produces specific arid inherent properties that are difficult to simulate with existing film-casting methods. The coating substrate or core material may have a decisive effect on coating material properties. Table-1: Shows the coating materials and applicable microencapsulation process. Coating Materials Water-soluble resins Multi - orific e centr ifuga l Phase separationcoacervatio n Pan coating Spray drying Air suspension Solvent evaporation Gelatin X X X X X X Gum Arabic X X X X X Starch X X X X Poly vinyl pyrollidone X X X X X Hydroxy ethyl cellulose X X X X Methyl cellulose X X X X X Arabinogalactan X X X X Poly vinyl alcohol X X X X X X Poly acyrlic acid X X X X X IJPT Jan-2013 Vol. 4 Issue No Page 2335

5 Water insoluble resins Ethyl cellulose X X X X X Polyethylene X X X X X X Polymethacrylate X X X X X Polyamide(nylon) X X X X X Poly [Ethylene-vinyl X X X X X acetate] Cellulose nitrate X X X X X Silcones X X X Poly (Lactide-co- X X X glycolide) Waxes and lipids Paraffin X X X X X Carnauba wax X X X Spermaceti X X X X Bees wax X X X Stearic acid X X Stearyl alcohol X X X Glyceryl stearates X X X Enteric resins X X X X Shellac Cellulose acetate phthalate X X X X X Zein X X MICROENCAPSULATION TECHNIQUES The microencapsulation techniques used include physical, physico chemical and chemical methods and are described as follows. [11,12,13] Fig.2 Shows the Representation of different microencapsulation techniques. IJPT Jan-2013 Vol. 4 Issue No Page 2336

6 PHYSICAL METHODS B.V.Subbaiah* et al. /International Journal Of Pharmacy&Technology PAN COATING The pan coating process, widely used in the pharmaceutical industry, is among the oldest industrial procedures for forming small, coated particles or tablets. The particles are tumbled in a pan or other device while the coating material is applied slowly. The pipe of the blower stretches into pot for an evenly heating distribution while the coating pan is rotating. [14] (Fig. 3) Fig. 3: Shows the conventional pan coating system. AIR-SUSPENSION COATING Micro-encapsulation by air suspension is a technique that gives improved control and flexibility s compared to pan coating. Solid, particulate core material is supported in a rising air stream and spray coating applied to the air suspended particles. The design of the coating chamber is arranged so that the solid particles pass up through the coating zone, then disperse into slower moving air and sink back to the base of the coating chamber, making repeated passes through the coating zone until the desired thickness of coating is achieved. The rising airstream is often heated to control the properties of the coating, often a polymer solution. [14] Fig.4: Shows the air-suspension coating. IJPT Jan-2013 Vol. 4 Issue No Page 2337

7 CENTRIFUGAL EXTRUSION B.V.Subbaiah* et al. /International Journal Of Pharmacy&Technology Liquids are encapsulated using a rotating extrusion head containing concentric nozzles. In this process, a jet of core liquid is surrounded by a sheath of wall solution or melt. As the jet moves through the air it breaks, owing to Rayleigh instability, into droplets of core, each coated with the wall solution. While the droplets are in flight, a molten wall may be hardened or a solvent may be evaporated from the wall solution. Since most of the droplets are within ± 10% of the mean diameter, they land in a narrow ring around the spray nozzle. Hence, if needed, the capsules can be hardened after formation by catching them in a ring-shaped hardening bath. This process is excellent for forming particles 400 2,000 µm (16 79 mils) in diameter. Since the drops are formed by the breakup of a liquid jet, the process is only suitable for liquid or slurry. A high production rate can be achieved, i.e., up to 22.5 kg (50 lb) of microcapsules can be produced per nozzle per hour per head. Heads containing 16 nozzles are available. VIBRATIONAL NOZZLE Core-Shell encapsulation or Micro granulation (matrix-encapsulation) can be done using a laminar flow through a nozzle and an additional vibration of the nozzle or the liquid. The vibration has to be done in resonance of the Rayleigh instability and leads to very uniform droplets. The liquid can consists of any liquids with limited viscosities (0-10,000 mpa s have been shown to work), e.g. solutions, emulsions, suspensions, melts etc. The solidification can be done according to the used gelation system with an internal gelation (e.g. sol-gel processing, melt) or an external (additional binder system, e.g. in a slurry). The process works very well for generating droplets between 100 5,000 µm ( mils), applications for smaller and larger droplets are known. The units are deployed in industries and research mostly with capacities of 1 10,000 kg per hour (2 22,000 lb/h) at working temperatures of C ( F) (room temperature up to molten silicon). Nozzles heads are available from one up to several hundred thousand are available. SPRAY DRYING Spray drying serves as a microencapsulation technique when an active material is dissolved or suspended in a melt or polymer solution and becomes trapped in the dried particle. The main advantages are the ability to handle labile materials because of the short contact time in the dryer, in addition, the operation is economical. In IJPT Jan-2013 Vol. 4 Issue No Page 2338

8 modern spray dryers the viscosity of the solutions to be sprayed can be as high as 300 mpa s. Applying This technique along with the use of supercritical Carbon Dioxide, also sensitive materials like proteins can be encapsulated. [15] Fig.5: Shows the spray drying. PHYSICO-CHEMICAL METHODS COACERVATION-PHASE SEPERATION TECHNIQUE The microencapsulation by coacervation-phase separation generally consists of three steps carried out under continuous agitation: (1) formation of three immiscible chemical phases, (2) deposition of coating, and (3) rigidization of the coating. The coacervation-phase separation has been classified into two categories, simple coacervation and complex coacervation. [16,17] IJPT Jan-2013 Vol. 4 Issue No Page 2339

9 Fig-6: Schematic representation of the coacervation process.(a) Core material dispersion in solution of shell polymer; (b) separation of coacervate from solution; (c) coating of core material by micro droplets of coacervate; (d) coalescence of coacervate to form continuous shell around core particles. The former implies addition of a strongly hydrophilic substance to a solution of colloid. This added substance causes two phases to be formed. The complex coacervation is principally a ph dependant process. The acidic or basic nature of the system is manipulated to produce microcapsules. Usually complex coacervation deals with the system containing more than one colloid (Fig. 6). Phase seperation is also known as Polymer - polymer incompatability which utilizes two polymers that are soluble in a common solvent, yet do not mix with one another in the solution. The polymers form two separate phases, one rich in the polymer intended to form the capsule walls, the other rich in the incompatible polymer meant to induce the separation of the two phases. The second polymer is not intended to be part of the finished microcapsule wall. SOLVENT EVAPORATION It is the most extensively used method of microencapsulation. Prepare an aqueous solution of the drug (may contain a viscosity building or stabilizing agent)then added to an organic phase consisting of the polymer solution in solvents like dichloromethane or chloroform with vigorous stirring to form the primary water in oil emulsion. This emulsion is then added to a large volume of water containing an emulsifier like PVA or PVP to form the multiple emulsion (w/o/w).the double emulsion is then subjected to stirring until most of the organic solvent evaporates, leaving solid microspheres. The microspheres can then be washed and dried.(fig.7). Fig. 7: Shows the Solvent evaporation technique. IJPT Jan-2013 Vol. 4 Issue No Page 2340

10 SOL-GEL ENCAPSULATION B.V.Subbaiah* et al. /International Journal Of Pharmacy&Technology Sol-gel encapsulation allows trapping lipophylic components inside the spherical shell of amorphous silicon dioxide. The process can be run, for example, in the oil-in-water (O/W) emulsion with an active material solubilized in the silicon phases such as tetraethoxysilane (TEOS) or tetramethoxysilane (TMOS). - Hydrolysis of the silicon droplets and condensation of the hydrolyzed species to silica occurs at the oil-water interface and leads to formation of the hard silica shell.(fig.8) Fig.8: Shows the Sol-gel encapsulation. SUPERCRITICAL CARBON DIOXIDE ASSISTED MICROENCAPSULATION Compressed carbon dioxide in the liquid or supercritical state is attractive as a solvent in microencapsulation processes. Carbon dioxide is non-toxic, non-flammable, and inexpensive. The high volatility of carbon dioxide allows it to be easily separated from polymeric materials by lowering pressure. - The supercritical fluid state is reached when the temperature and pressure of a substance are above its critical temperature and pressure. For carbon dioxide, the critical temperature is 31 C and the critical pressure is 74 bar. Phase diagram of CO 2. Generally there are three steps in the impregnation: First, the polymer materials are exposed to supercritical CO 2 for a while; then the solution of additives in CO 2 is introduced and the solute is transferred from CO 2 to polymer - Last, CO 2 is released and the solute is trapped in the polymer material. - When suspensions of polymer particles in water are exposed to supercritical CO 2 with the presence of additives in water, the transport of the additive into polymer particles can also be enhanced. After releasing CO 2, additives can be trapped in colloidal polymer particles. IJPT Jan-2013 Vol. 4 Issue No Page 2341

11 Fig.9: Shows the supercritical carbon dioxide assisted microencapsulation. CHEMICAL METHODS INTERFACIAL POLYCONDENSATION In Interfacial polycondensation, 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 anacid 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. INTERFACIAL CROSS-LINKING Interfacial cross-linking is derived from interfacial polycondensation, and was developed to avoid the use of toxic diamines, for pharmaceutical or cosmetic applications. In this method, the small bifunctional monomer containing active hydrogen atoms is replaced by a biosourced polymer, like a protein. When the reaction is performed at the interface of an emulsion, the acid chloride reacts with the various functional groups of the protein, leading to the formation of a membrane. The method is very versatile, and the properties of the microcapsules (size, porosity, degradability, mechanical resistance). Flow of artificial microcapsules in microfluidic channels. [18] 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 µm ( mils). [19] The coating is uniform, even over sharp projections. Protein microcapsules are biocompatible and biodegradable, and the presence of IJPT Jan-2013 Vol. 4 Issue No Page 2342

12 the protein backbone renders the membrane more resistant and elastic than those obtained by interfacial polycondensation. [20] 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. MECHANISMS OF DRUG RELEASE Major mechanisms of drug release from microcapsules are as follows 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 as 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, 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 [21, 22] glyceryl mono staterate, beeswax and steryl alcohol etc. Table.2: Shows the microencapsulation processes and their applicabilities. Microencapsulation Process Applicable core material Particle size (micrometers) Air suspension Solids Coacervation-phase Separation Solids & liquids Multiorifice centrifugal Solids & liquids Pan coating Solids IJPT Jan-2013 Vol. 4 Issue No Page 2343

13 Solvent evaporation Solids & liquids Spray drying Solids & liquids 600 *The 5000 µm size is not a particle limitation; the methods are also applicable to macro coating CONCLUSION: [1, 10, 23] The microencapsulation techniques offers a variety of opportunities such as protection and masking, reduced dissolution rate, facilitation of handling and spatial targeting of the active ingredients. This approach facilitates accurate delivery of small quantities of potent drugs, reduced drug concentrations at sites other than the target organ or tissue and protection of labile compounds before and after administration and prior to appearance at the site of action. In future by combining various other approaches, microencapsulation technique will find the vital role in novel drug delivery system. References: 1. Bakan, J.A. (1986) Microencapsulation IN.LIberman, H.A etal. (Eds) The theory and practice of industrial pharmacy, 3 rd edition, p.no Swapan Kumar Ghosh Functional coatings and Microencapsulation. General perspectives WILEY-VCH Verlag Gmbh and Co. KGaA, weinheim.isbn x. 3. Hammad umer.microencapsulation: process, techniques, applications. International journal of research in pharmaceutical and biomedical sciences.issn: Finch CA, Polymers for microcapsule walls. Chem. Ind. 1985; 22: Li SP, Kowarski CR, Feld KM and Grim WM Recent advances in microencapsulation technology and equipment. Drug Dev. Ind. Pharm., 1988; 14: Ghulam Murtaza, Mahmood Ahamd, Naveed Akhtar and Fatima Rasool. A comparative Study of various microencapsulation techniques: effect of polymer viscosity on microcapsule characteristics. Pak. J. Pharm. Sci. 2009; 3: N.K.Jain. Controlled and Novel drug delivery. 04th edition S.P.Vyas and R.K.Khar, Targeted and Controlled drug delivery. 07th edition Nikhil.K.Sachan. Malaysiam journal of pharmaceutical sciences.vol 4. NO. 1, 65-81(2006). IJPT Jan-2013 Vol. 4 Issue No Page 2344

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15 23. Wurster DE. Particle-coating methods. In: Lieberman HA, Lachman L, Schwartz JB. (Eds). Pharmaceutical Dosage Forms: Tablets.Vol. 3, 2nd edition, Marcel Dekker: New York (1990) pp Reilly W.J.; Remington: The Science and Practice of Pharmacy, 20th edition, Mack Publishing company, 2002, PP Thies C. A survey of microencapsulation processes, Simon Benita, micro-encapsulation and industrial applications, Ch 1. Maecel Dekker Imp.New York. 26. HERMAN NACK, B.Ch.E. Microencapsulation Techniques Applications and Problems, J. $oc. Cosmetic Chemists, 21, (Feb. 4, DEASY, P. B. (1984) Microencapsulation and Related Drug Processes (New York: Marcel Dekker). 28. Ghosh SK. Functional coatings and microencapsulation: A General Perspective. In: Ghosh SK (Ed). Functional Coating by Polymer Microencapsulation. Wiley-Vch Verlag GmbH & Co. KGaA: Weinheim (2006) pp M.M. Gutcho, Microcapsules and Microecapsulation Techniques, Noyes Data Co., New Jersey, USA, J.E. Vandegaer, Microencapsulation: Processes and Applications, Plenum Press, New York, S. Benita, Microencapsulation: Methods and Industrial applications, Marcel Dekker, Inc., New York, Corresponding Author: B.V.Subbaiah*, bodepudivenkatasubbaiah@gmail.com IJPT Jan-2013 Vol. 4 Issue No Page 2346