A Project Report on Microencapsulation

2011

INTRODUCTION
Microencapsulation is a process by which solids, liquids or even gases may be enclosed in microscopic particles formation of thin coatings of wall material around the substances. The process had its origin in the late 1930s as a cleaner substitute for carbon paper and carbon ribbons as sought by the business machines industry. The ultimate development in the 1950s of reproduction paper and ribbons that contained dyes in tiny gelatin capsules released on impact by a typewriter key or the pressure of a pen or pencil was the stimulus for the development of a host of microencapsulated materials, including drugs (Allen et al., 2005) A well designed controlled drug delivery system can overcome some of the problems of conventional therapy and enhance the therapeutic efficacy of a given drug. To obtain maximum therapeutic efficacy, it becomes necessary to deliver the agent to the target tissue in the optimal amount in the right period of time there by causing little toxicity and minimal side effects. There are various approaches in delivering a therapeutic substance to the target site in a sustained controlled release fashion. One such approach is using microspheres as carriers for drugs. Microspheres are characteristically free flowing powders consisting of protiens or synthetic polymers which are biodegradable in nature and ideally having particle size less than 200 m [3]. Microencapsulation is a process by which very tiny droplets or particles of liquid or solid material are surrounded or coated with a continuous film of polymeric material. Microencapsulation includes Bioencapsulation which is more restricted to the entrapment of a biologically active substance (from DNA to entire cell or group of cells for example) generally to improve its performance &/or enhance its shelf life (Vyas and Khar). Microencapsulation provides the means of converting liquids to solids, of altering colloidal and surface properties, of providing environmental protection and of controlling the release characteristics or availability of coated materials.
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Several of these properties can be attained by macropackaging techniques; however, the uniqueness of microencapsulation is the smallness of the coated particles and their subsequent use and adaptation to a wide variety of dosage forms and not has been technically feasible.

Fig: 1- Microencapsulation process This technique can be used for converting liquid drugs in a free flowing powder. The drugs, which are sensitive to oxygen, moisture or light, can be stabilized by microencapsulation. Incompatibility among the drugs can be prevented by microencapsulation. Vaporization of many volatile drugs e.g. methyl salicylate and peppermint oil can be prevented by microencapsulation. Many drugs have been microencapsulated to reduce toxicity and GI irritation including ferrous sulphate and KCl. Alteration in site of absorption can also be achieved by microencapsulation.
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Toxic chemicals such as insecticides may be microencapsulated to reduce the possibility of sensitization of factorial person. Bakan and Anderson reported that microencapsulated vitamin A palmitate had enhanced stability (James, 2005)

The Reasons for Microencapsulation

The reasons for microencapsulation are countless. In some cases, the core must be isolated from its surroundings, as in isolating vitamins from the deteriorating effects of oxygen, retarding evaporation of a volatile core, improving the handling properties of a sticky material, or isolating a reactive core from chemical attack. In other cases, the objective is not to isolate the core completely but to control the rate at which it leaves the microcapsule, as in the controlled release of drugs or pesticides. The problem may be as simple as masking the taste or odor of the core, or as complex as increasing the selectivity of an adsorption or extraction process.

Fig: 2- microsphere & microcapsule.

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A Project Report on Microencapsulation

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FUNDAMENTAL CONSIDERATIONS
The realization of the potential that microencapsulation offers involves a basic understanding of the general properties of microcapsules, such as the nature of the core and coating materials, the stability and release characteristics of the coated materials and the microencapsulation methods (Lachman).

RELEASE MECHANISMS
Mechanisms of drug release from microspheres are

1. Degradation controlled monolithic system

The drug is dissolved in matrix and is distributed uniformly throughout. The drug is strongly attached to the matrix and is released on degradation of the matrix. The diffusion of the drug is slow as compared with degradation of the matrix.

2. Diffusion controlled monolithic system

Here the active agent is released by diffusion prior to or concurrent with the degradation of the polymer matrix. Rate of release also depend upon where the polymer degrades by homogeneous or heterogeneous mechanism.

3. Diffusion controlled reservoir system

Here the active agent is encapsulated by a rate controlling membrane through which the agent diffuses and the membrane erodes only after its delivery is completed. In this case, drug release is unaffected by the degradation of the matrix.

4. Erosion
Erosion of the coat due to pH and enzymatic hydrolysis causes drug release with certain coat material like glyceryl mono stearate, beeswax and steryl alcohol etc (Cassidy et al., 1993).

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CORE MATERIALS
The core material, defined as the specific material to be coated, can be liquid or solid in nature. The composition of the core material can be varied, as the liquid core can include dispersed and/or dissolved materials. The solid core be active constituents, stabilizers, diluents, excipients, and release-rate retardants or accelerators. The ability to vary the core material composition provides definite flexibility and utilization of this characteristics often allows effectual design and development of the desired microcapsule properties (Leon et al., 1990).

COATING MATERIALS
The selection of appropriate coating material decides the physical and chemical properties of the resultant microcapsules/microspheres. While selecting a polymer the product requirements ie. Stabilization, reduced volatility, release characteristics, environmental conditions, etc. should be taken into consideration. The polymer should be capable of forming a film that is cohesive with the core material. It should be chemically compatible, non-reactive with the core material and provide the desired coating properties such as strength, flexibility, impermeability, optical properties and stability. Generally hydrophilic polymers, hydrophobic polymers (or) a combination of both are used for the microencapsulation process. A number of coating materials have been used successfully; examples of these include gelatin, polyvinyl alcohol, ethyl cellulose, cellulose acetate phthalate and styrene maleic anhydride. The film thickness can be varied considerably depending on the surface area of the material to be coated and other physical characteristics of the system. The microcapsules may consist of a single particle or clusters of particles. After isolation from the liquid manufacturing vehicle and drying, the material appears as a free flowing powder. The powder is suitable for formulation as compressed tablets, hard gelatin capsules, suspensions, and other dosage forms.
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The coating material should be capable of forming a film that is cohesive with the core material; be chemically compatible and nonreactive with the core material; and provide the desired coating properties, such as strength, flexibility, impermeability, optical properties, and stability. The coating materials used in microencapsulation methods are amenable, to some extent, to in situ modification. 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 freefilm information often is impeded for the following reasons: Cast or free films prepared by the usual casting techniques yield films that are considerably thicker than those produced by the microencapsulation of small particles; hence, the results obtained from the cast films may not be extrapolate to the thin microcapsule coatings. The particular microencapsulation method employed for the deposition of a given coating produces specific and inherent properties that are difficult to simulate with existing film-casting methods. The coating substrate of core material may have a decisive effect on coating properties. Hence, the selection of a particular coating material involves consideration of both classic free-film data and applied results (Venkatesan et al., 2009).

Coating material properties

Stabilization of core material. Inert toward active ingredients. Controlled release under specific conditions. Film-forming, pliable, tasteless, stable. Non-hygroscopic, no high viscosity, economical. Soluble in an aqueous media or solvent, or melting. The coating can be flexible, brittle, hard, thin etc.

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Examples of coating materials:

Water soluble resins Gelatin, Gum Arabic, Starch, Polyvinylpyrrolidone, Carboxymethylcellulose, Hydroxyethylcellulose,

Methylcellulose, Arabinogalactan, Polyvinyl alcohol, Polyacrylic acid. Water insoluble resins Ethylcellulose, Polyethylene, Polymethacrylate, Polyamide (Nylon), Poly (Ethylene Vinyl acetate), Cellulose nitrate, Silicones, Poly(lactideco glycolide). Waxes and lipids Paraffin, Carnauba, Spermaceti, Beeswax, Stearic acid, Stearyl alcohol, Glyceryl stearates . Enteric resins Shellac, Cellulose acetate phthalate, Zein (Lopez et al 1998).

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TECHNIQUES TO MANUFACTURE MICROCAPSULES

Preparation of microspheres should satisfy certain criteria: The ability to incorporate reasonably high concentrations of the drug. Stability of the preparation after synthesis with a clinically acceptable shelf life. Controlled particle size and dispersability in aqueous vehicles for injection. Release of active reagent with a good control over a wide time scale. Biocompatibility with a controllable biodegradability and Susceptibility to chemicalmodification.

Fig: 3- Microencapsulation techniques

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Physical methods
Air-suspension coating
Microencapsulation by air suspension technique consist of the dispersing of solid, particulate core materials in a supporting air stream and the spray coating on the air suspended particles. Within the coating chamber, particles are suspended on an upward moving air stream. The design of the chamber and its operating parameters effect a recirculating flow of the particles through the coating zone portion of the chamber, where a coating material, usually a polymer solution, is spray applied to the moving particles. During each pass through the coating zone, the core material receives an increment of coating material. The cyclic process is repeated, perhaps several hundred times during processing, depending on the purpose of microencapsulation the coating thickness desired or whether the core material particles are thoroughly encapsulated. The supporting air stream also serves to dry the product while it is being encapsulated. Drying rates are directly related to the volume temperature of the supporting air stream. Air-suspension coating of particles by solutions or melts gives better control and flexibility. The particles are coated while suspended in an upward-moving air stream. They are supported by a perforated plate having different patterns of holes inside and outside a cylindrical insert. Just sufficient air is permitted to rise through the outer annular space to fluidize the settling particles. Most of the rising air (usually heated) flows inside the cylinder, causing the particles to rise rapidly. At the top, as the air stream diverges and slows, they settle back onto the outer bed and move downward to repeat the cycle. The particles pass through the inner cylinder many times in a few minutes methods. The air suspension process offers a wide variety of coating materials candidates for microencapsulation. The process has the capability of applying coatings in the form of solvent solutions, aqueous solution, emulsions, dispersions or hot melts in equipment ranging in capacities from one pound to 990 pounds. Core
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materials comprised of micron or submicron particles can be effectively encapsulated by air suspension techniques, but agglomeration of the particles to some larger size is normally achieved (Jackson & Lee, 1991).

Coacervation Process
Solution of the shell material in water. Example: Copolymer coating Gum arabic solution 20-30% Gelatin solution 20% Preparation The core material will be added to the solution. The core material should not react or dissolve in water (maximum solubility 2%) Dispersion The core material is dispersed in the solution. The particle size will be defined by dispersion parameter, as stirring speed, stirrer shape, surface tension and viscosity. Size range ca. 2m - 1200m Coacervation Coacervation starts with a change of the pH value of the dispersion, e.g. by adding H2SO4, HCl or organic acids. The result is a reduction of the solubility of the dispersed phases (shell material). The shell material (coacervate) starts to precipitate from the solution. The shell material forms a continuous coating around the core droplets. Cooling and hardening phase The shell material is cooled down to harden and forms the final capsule. Hardening agents like formaldehyde can be added to the process. The microcapsules are now stable in the suspension and ready to be dried. Drying phase The suspension is dried in a spray dryer or in a fluidized bed drier.
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Spray Drying is a suitable method for heat sensitive Products. The atomized particles assume a spherical shape. The rapid the coating material keeps the core material below 100C, even if the temperature in the drying chamber is much greater. Microencapsulation makes the spray drying process easier for sticky products like fruit pulp or juice, with a high content of invert sugar (). Coacervation-Phase Separation The general outline of the processes consists of three steps carried out under continuous agitation: 1. Formation of three immiscible chemical phases A liquid manufacturing vehicle phase, a core material phase, and a coating material phase. To form the three phases, the core material dispersed in a solution of the coating polymer, the solvent for the polymer being the liquid manufacturing vehicle phase. The coating material phase, an immiscible polymer in a liquid state, is formed by utilizing one of the methods of the methods of phase separation-coacervation, i.e., by changing the temperature of the polymer solution; or by adding a salt, nonsolvent, or incompatible polymer to the polymer solution; or by inducing a polymerpolymer interaction. 2. Deposition of the coating It consists of depositing the liquid polymer coating upon the core material. This is accomplished by controlled, physical mixing of the material in the manufacturing vehicle. 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. The continued deposition of the coating material is promoted by a reduction in the total free interfacial energy of the system, brought about by the decrease of the coating material surface area during coleasance of the liquid polymer droplets. 3. Rigidization of the coating It involves rigidizing the coating, usually by thermal, cross-linking, or desolvation techniques, to form a self-sustaining microcapsules

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eg. Coacervation Microencapsulation of Talc Particles with Poly (methyl methacrylate) by Pressure-Induced Phase Separation of CO2-Expanded Ethanol Solution (Fang-Jing Wang & Chi-Hwa Wang, 2002).

Centrifugal extrusion
Liquids are encapsulated using a rotating extrusion head containing concentric nozzles. In this process, a jet of core liquid is surrounded by a sheath of wall solution or melt. As the jet moves through the air it breaks, owing to Rayleigh instability, into droplets of core, each coated with the wall solution. While the droplets are in flight, a molten wall may be hardened or a solvent may be evaporated from the wall solution. Since most of the droplets are within 10% of the mean diameter, they land in a narrow ring around the spray nozzle. Hence, if needed, the capsules can be hardened after formation by catching them in a ringshaped hardening bath. This process is excellent for forming particles 400 2,000 m (1679 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 (Guo, 1994).

Pan coating
The pan coating process, widely used in the pharmaceutical industry, is among the oldest industrial procedures for forming small, coated particles or tablets. The particles are tumbled in a pan or other device while the coating material is applied slowly. The pan coating process, widely used in the pharmaceutical industry, is among the oldest industrial procedures for forming small, coated particles or tablets. The particles are tumbled in a pan or other device while the coating material is applied slowly with respect to microencapsulation, solid particles greater than
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600 microns in size are generally considered essential for effective coating, and the process has been extensively employed for the preparation of controlled release beads. Medicaments are usually coated onto various spherical substrates such as nonpareil sugar seeds, and then coated with protective layers of various polymers.

Fig: 4-Representation of a typical pan coating In practice, the coating is applied as a solution, or as an atomized spray, to the desired solid core material in the coating pans. Usually, to remove the coating solvent, warm air is passed over the coated materials as the coatings are being applied in the coating pans. In some cases, final solvent removal is accomplished in a drying oven (Dortune et al., 1998).

Fig: 5- List of variables affecting pan coating process

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Spraydrying

2011

Spray drying serves as a microencapsulation technique when an active material is dissolved or suspended in a melt or polymer solution and becomes trapped in the dried particle. The main advantages is the ability to handle labile materials because of the short contact time in the dryer, in addition, the operation is economical. In modern spray dryers the viscosity of the solutions to be sprayed can be as high as 300mPa.s Spray drying and spray congealing processes are similar in that both involve dispersing the core material in a liquefied coating substance and spraying or introducing the core coating mixture into some environmental condition, whereby, relatively rapid solidification (and formation) of the coating is affected. The principal difference between the two methods is the means by which coating solidification is accomplished. Coating solidification in the case of spray drying is effected by rapid evaporation of a solvent in which the coating material is dissolved. Coating solidification in spray congealing methods, however, is accomplished by thermally congealing a molten coating material or by solidifying a dissolved coating by introducing the coating - core material mixture into a non-solvent. Removal of the non-solvent or solvent from the coated product is then accomplished by sorption, extraction, or evaporation techniques. In practice, microencapsulation by spray drying is conducted by dispersing a core material in a coating solution, in which the coating substance is dissolved and in which the core material is insoluble, and then by atomizing the mixture into air stream. The air, usually heated, supplies the latent heat of vaporization required to remove the solvent from the coating material, thus forming the microencapsulated product. The equipment components of a standard spray dryer include an air heater, atomizer, main spray chamber, blower or fan, cyclone and product collector. Microencapsulation by spray congealing can be accomplished with spray drying equipment when the protective coating is applied as a melt. General process variables and conditions are quite similar to
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those already described, except that the core material is dispersed in a coating material melt rather than a coating solution. Coating solidification (and microencapsulation) is accomplished by spraying the hot mixture into a cool air stream. Waxes, fatty acids and alcohols, polymers and sugars, which are solids at room temperature but meltable at reasonable temperatures, are applicable to spray congealing techniques. Typically, the particle size of spray congealed products can be accurately controlled when spray drying equipment is used, and has been found to be a function of the feed rate, the atomizing wheel velocity, dispersion of feed material viscosity, and variables (Collins & Deasy, 1990). Airflow The initial contact between spray droplets and drying air controls evaporation rates and product temperatures in the dryer. There are three modes of contact: Co-current Drying air and particles move through the drying chamber in the same direction. Product temperatures on discharge from the dryer are lower than the exhaust air temperature, and hence this is an ideal mode for drying heat sensitive products. When operating with rotary atomizer, the air disperser creates a high degree of air rotation, giving uniform temperatures throughout the drying chamber. However, an alternative non-rotating airflow is often used in tower or FILTERMAT-type spray dryers using nozzle atomizers with equal success. Counter-current Drying air and particles move through the drying chamber in opposite directions. This mode is suitable for products which require a degree of heat treatment during drying. The temperature of the powder leaving the dryer is usually higher than the exhaust air temperature. Mixed-flow Particle movement through the drying chamber experiences both co-current and counter-current phases. This mode is suitable for heat stable products

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where coarse powder requirements necessitate the use of nozzle atomizers, spraying upwards into an incoming airflow, or for heat sensitive products where the atomizer sprays droplets downwards towards an integrated fluid bed and the air inlet and outlet are located at the top of the drying chamber. eg. Study on microencapsulation of lycopene by spraydrying (Alagusundaram et al., 2009).

Chemical methods
Solvent Evaporation
This technique has been used by companies including the NCR Company, Gavaert Photo - Production NV, and Fuji Photo Film Co., Ltd. to produce microcapsules. The processes are carried out in a liquid manufacturing vehicle. The microcapsule coating is dissolved in a volatile solvent, which is immiscible with the liquid manufacturing vehicle phase. A core material to be microencapsulated is dissolved or dispersed in the coating polymer solution. With agitation, the core coating material mixture is dispersed in the liquid manufacturing vehicle phase to obtain the appropriate size microcapsule. The mixture is then heated (if necessary) to evaporate the solvent for the polymer. In the case in which the core material is dispersed in the polymer solution, polymer shrinks around the core. In the case in which core material is dissolved in the coating polymer solution, a matrix - type microcapsule is formed. Once all the solvent for the polymer is evaporated, the liquid vehicle temperature is reduced to ambient temperature (if required) with continued agitation. At this stage, the microcapsules can be used in suspension form, coated on to substrates or isolated as powders. The solvent evaporation technique to produce microcapsules is applicable to a wide variety of liquid and solid core materials. The core materials may be either water soluble or water insoluble materials. A variety of film forming polymers can be used as coatings

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eg. Evaluation of of Sucrose Proteins Esters by as the Alternative Solvent

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Surfactants in

Microencapsulation

Evaporation

Method

(Hausberger & Deluca 1995).

Polymerization
In this technique the capsule shell will be formed at or on the surface of the droplet or particle by polymerization of the reactive monomers. The substances used are multifunctional monomers. Generally used monomers include multifunctional isocyanates and multifunctional acid chlorides. These will be used either individually or in combination. The multifunctional monomer dissolved in liquid core material and it will be dispersed in aqueous phase containing dispersing agent. A coreactant multifunctional amine will be added to the mixture. This results in rapid polymerization at interface and generation of capsuleshell takes place. A polyurea shell will be formed when isocyanate reacts with amine, polynylon or polyamide shell will be formed when acid chloride reacts with amine. When isocyanate reacts with hydroxyl containing monomer produces polyurethane shell. Like IFP the capsule shell formation occurs because of polymerization monomers added to the encapsulation reactor. In this process no reactive agents are added to the core material, polymerization occurs exclusively in the continuous phase and on the continuous phase side of the interface formed by the dispersed core material and continuous phase. Initially a low molecular weight prepolymer will be formed, as time goes on the prepolymer grows in size, it deposits on the surface of the dispersed core material there by generating solid capsule shell. E.g. encapsulation of various water immiscible liquids with shells formed by the reaction at acidic pHof urea with formaldehyde in aqueous media Interfacial polymer In Interfacial polymerization, the two reactants in a polycondensation meet at an interface and react rapidly. The basis of this method is the classical Schotten Baumann reaction between an acid chloride and a compound
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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 0.5m/min. Coating thickness ranges 0.2-75m. The coating is uniform, even over sharp projections. Matrix polymer In a number of processes, a core material is imbedded in a polymeric matrix during formation of the particles. A simple method of this type is spray-drying, in which the particle is formed by evaporation of the solvent from the matrix material. However, the solidification of the matrix also can be caused by a chemical change. Using this phenomenon, Chang prepares microcapsules containing protein solutions by incorporating the protein in the aqueous diamine phase. Chang has demonstrated the permselectivity, by their ability to convert blood urea to ammonia, the enzyme remaining within the microcapsules when incorporated within an extracorporeal shunt system. Numerous groups are utilizing polymerization techniques to accomplish microencapsulation. Examples are the National Lead Corporation, Eurand Americ (Chein & Novir, 1996).

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APPLICATION OF MICROENCAPSULATION
There are many reasons why drugs and related chemicals have been microencapsulated. The technology has been used widely in the design of controlled release and sustained release dosage forms.

Fig: 6- Applications of microencapsulation To mask the bitter taste of drugs like Paracetamol, Nitrofurantoin etc. Many drugs have been microencapsulated to reduce gastric and other G.I. tract irritations. Sustained release Aspirin preparations have been reported to cause significantly less G.I. bleeding than conventional preparations. A liquid can be converted to a pseudo-solid for easy handling and storage. eg.Eprazinone.

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Hygroscopic properties of core materials may be

2011
reduced by

microencapsulation eg. Sodium chloride. Carbon tetra chlorides and a number of other substances have been microencapsulated to reduce their odor and volatility. Microencapsulation has been employed to provide protection to the core materials against atmospheric effects, e.g. Vit.A.Palmitate. Separation of incompatible substance has been achieved by

encapsulation. Cell immobilization: In plant cell cultures, Human tissue is turned into bio-artificial organs, in continuous fermentation processes. Beverage production Protection of molecules from other compounds Drug delivery: Controlled release delivery systems. Quality and safety in food, agricultural & environmental sectors. Soil inoculation. In textiles: means of imparting finishes. Protection of liquid crystals (Kesting, 1985).

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CHARACTERIZATION OF MICROCAPSULE
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.

SIEVE ANALYSIS
Separation of the microspheres into various size fractions can be determined by using a mechanical sieve shaker (Sieving machine, Retsch, Germany). A series of five standard stainless steel sieves (20, 30, 45, 60 and 80 mesh) are arranged in the order of decreasing aperture size. Five grams of drug loaded microspheres are placed on the upper-most sieve. The sieves are shaken for a period of about 10 min, and then the particles on the screen are weighed (PaoChu et al., 2003).

MORPHOLOGY OF MICROSPHERES
The surface morphologies of microspheres are examined by a scanning electron microscope (XL 30 SEM Philips, Eindhoven, and The Netherlands). The microspheres are mounted onto a copper cylinder (10 mm in diameter, 10 mm in height) by using a double-sided adhesive tape. The specimens are coated at a current of 10 mA for 4 min using an ion sputtering device (JFC-1100E, Jeol, Japan) (Venkatesh, 1989).

ATOMIC FORCE MICROSCOPY (AFM)

A Multimode Atomic Force Microscope from Digital Instrument is used to study the surface morphology of the microspheres. The samples are mounted on metal slabs using double-sided adhesive tapes and observed under microscope that is maintained in a constant-temperature and vibration-free environment (Schugens et al., 1994).

PARTICLE SIZE
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Particle size determination approximately 30 mg microparticles is redispersed in 23 ml distilled water, containing 0.1% (m/m) Tween 20 for 3 min, using ultrasound and then transferred into the small volume recirculating unit, operating at 60 ml/s. The microparticle size can be determined by laser diffractometry using a Malvern Mastersizer X (Malvern Instruments, UK) (Tanaka et al., 1977).

POLYMER SOLUBILITY IN THE SOLVENTS

Solution turbidity is a strong indication of solvent power [14]. The cloud point can be used for the determination of the solubility of the polymer in different organic solvents (Parodi et al., 1996).

VISCOSITY OF THE POLYMER SOLUTIONS

The absolute viscosity, kinematic viscosity, and the intrinsic viscosity of the polymer solutions in different solvents can be measured by a U-tube viscometer (viscometer constant at 40 0C is 0.0038 mm2/s /s) at 25 0.1 0C in a thermostatic bath. The polymer solutions are allowed to stand for 24 h prior to measurement to ensure complete polymer dissolution (Yi-Yan Yang et al., 2000).

DENSITY DETERMINATION
The density of the microspheres can be measured by using a multi volume pychnometer. Accurately weighed sample in a cup is placed into the multi volume pychnometer. Helium is introduced at a constant pressure in the chamber and allowed to expand. This expansion results in a decrease in pressure within the chamber. Two consecutive readings of reduction in pressure at different initial pressure are noted. From two pressure readings the volume and density of the microsphere carrier is determined (Nagai et al., 1980).

BULK DENSITY
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The microspheres fabricated are weighed and transferred to a 10-ml glass graduated cylinder. The cylinder is tapped using an autotrap (Quantach- rome, FL, USA) until the microsphere bed volume is stabilised. The bulk density is estimated by the ratio of microsphere weight to the final volume of the tapped microsphere bed (ODonnell & McGinity, 1997).

CAPTURE EFFICIENCY
The capture efficiency of the microspheres or the percent entrapment can be determined by allowing washed microspheres to lyse. The lysate is then subjected to the determination of active constituents as per monograph requirement.The percent encapsulation efficiency is calculated using following equation: % Entrapment = Actual content/Theoretical content x 100

ANGLE OF CONTACT
The angle of contact is measured to determine the wetting property of a micro particulate carrier. It determines the nature of microspheres in terms of hydrophilicity or hydrophobicity. This thermodynamic property is specific to solid and affected by the presence of the adsorbed component. The angle of contact is measured at the solid/air/water interface. The advancing and receding angle of contact are measured by placing a droplet in a circular cell mounted above objective of inverted microscope. Contact angle is measured at 200C within a minute of deposition of microspheres (Ishida et al., 1983).

IN VITRO METHODS
There is a need for experimental methods which allow the release characteristics and permeability of a drug through membrane to be determined. For this purpose, a number of in vitro and in vivo techniques have

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been reported. In vitro drug release studies have been employed as a quality control procedure in pharmaceutical production, in product development etc. Sensitive and reproducible release data derived from physico chemically and hydro dynamically defined conditions are necessary. The influence of technologically defined conditions and difficulty in simulating in vivo conditions has led to development of a number of in vitro release methods for buccal formulations; however no standard in vitro method has yet been developed. Different workers have used apparatus of varying designs and under varying conditions, depending on the shape and application of the dosage form developed (Fabregas & Garcia, 1995).

BEAKER METHOD
The dosage form in this method is made to adhere at the bottom of the beaker containing the medium and stirred uniformly using over head stirrer. Volume of the medium used in the literature for the studies varies from 50-500 ml and the stirrer speed form 60-300 rpm (Chien et al., 1991).

DISSOLUTION APPARATUS
Standard USP or BP dissolution apparatus have been used to study in vitro release profiles using both rotating elements, paddle [20, 21, 22 and basket 23, 24]. Dissolution medium used for the study varied from 100-500 ml and speed of rotation from 50-100 rpm.

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ADVANTAGES
Reliable means to deliver the drug to the target site with specificity, if modified, and to maintain the desired concentration at the site of interest without untoward effects. Solid biodegradable microspheres have the potential throughout the particle matrix for the controlled release of drug. Microspheres received much attention not only for prolonged release, but also for targeting of anticancer drugs to the tumour. The size, surface charge and surface hydrophilicity of microspheres have been found to be important in determining the fate of particles in vivo. Studies on the macrophage uptake of microspheres have demonstrated their potential in targeting drugs to pathogens residing intracellularly (Rao et al., 2009).

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poly(D,Llactide-co-glycolide) polymers and micro- spheres J. Pharm. Biomed. Anal. (1995). 13: 747760. Ishida, M, Nambu N, Nagai T. Highly viscous gel ointment containing carbapol for application to the oral mucosa. Chem. pharm Bull. (1983). 31:4561. Jackson, LS and Lee K. Microencapsulation and the food industry (htm) Lebennsmittel-Wissenschaft Release. (1991). 5: 199-205. James S. Encylopedia of PharmaceuticalTechonology. (2005). 3: 13251333. Kesting RE. Synthetic Polymeric Membranes, A Structural Perspective A Wiley-Interscience Publication, Wiley. (1985) 2nd Edition: 525. Lachman LA, Liberman HA, Kanig JL. The Theory and Practice of Industrial Pharmacy. Mumbai, India: Varghese Publishng House. 3:414415. Leon, L, Herbert AL, Joseph LK. The Theory And Practice Of Industrial Pharmacy. Varghese Publishing House. (1990). 3: 412-428. Lopez, CR, Portero A, Vila-Jato, JC, Alonso MJ. Design and Evaluation of Chitosan/Ethylcellulose mucoadhesive bilayered devices for buccal drug delivery.J.control.Rel. (1998). 55: 143-152. Nagai T, Machida Y, Suzuki Y, Ikura H. Method & preparation for administration to the mucosa & preparation for administration to the mucosa of the oral or nasal cavity US patent NO.4226848. (1980). ODonnell PB, McGinity JW. Preparation of microspheres by solvent evaporation technique. Advanced Drug Delivery Reviews. (1997). 28:2542. Pao-Chu Wua, Yaw-Bin Huanga, Jui- Sheng Changa, Ming-Jun Tsaib, Yi-Hung Tsaia. Design and evaluation of sustained release microspheres Techonologie. Rerrived on Controlled

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of potassium chloride prepared by Eudragit. Euro. J. of Pharma. Sciences. (2003). 19: 115122. Parodi, B, Russo E, Caviglioli G, Cafaggi S, Binardi G. Development &characterization of a buccoadhesive dosage form of Oxydodone hydrochloride. Drug Dev.Ind.pharm. (1996) 22: 445-450. Rao MRP, Borate SG, Thanki KC, Ranpise AA, Parikh GN. Development and in vitro evaluation of floating rosiglitazone maleate microspheres Drug development and Industrial pharmacy. (2009). 35: 834-842. Schugens C, Larvelle N, Nihantn S, Grandfils C, Jerome R, Teyssie P. P. J.Control.Rel. (1994). 32:161. Tanaka W, Akito E, Yoshida K, Terada T, Ninomiya H. pharmaceutical preparations for oral cavity administration US patent No.4059686. (1977). Venkatesan P, Muralidharan C, Manavalan R, Valliappan K. Selection of better method for the preparation of microspheres by applying Analytic Hierarchy Process. J. Pharm. Sci. & Res. (2009). 1: 64-78. Venkatesh H. A buccal delivery system of Salbutamol Sulphate. J. Pharm. Sci. & Res. (1989). 3: 53-55 Vyas SP and Khar RK. Targeted and Controlled drug delivery, 07 Edition: 418. Yi-Yan Yang, Hui-Hui Chia , Tai-Shung Chung. Effect of preparation temperature on the characteristics and release profiles of PLGA microspheres containing protein fabricated by double-emulsion solvent extraction / evaporation method. Journal of Controlled Release. (2000). 69: 8196

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