Microencapsulation Microencapsulation is a process or technique by which thin coatings can be applied reproducibly to small particles of solids, droplets of liquids, or dispersions, thus, forming microcapsules. It can be differentiated readily from other coating methods in the size of the particles involved; these range from several tenths to about 5000 micrometers in size. 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. Several of these properties can be attained by macro packaging 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. This technique can be used for 1. Converting liquid drugs in a free flowing powder. 2. The drugs, which are sensitive to oxygen, moisture or light, can be stabilized by microencapsulation. 3. Incompatibility among the drugs can be prevented by microencapsulation. 4. Vaporization of many volatile drugs e.g. methyl salicylate and peppermint oil can be prevented by microencapsulation. 5. Many drugs have been microencapsulated to reduce toxicity and GI irritation including ferrous sulphate and KCl. 6. Alteration in site of absorption can also be achieved by microencapsulation. 7. Toxic chemicals such as insecticides may be microencapsulated to reduce the possibility of sensitization of factorial person. The microparticle system has become an indispensable part of the controlled drug delivery fields for the past few decades since it can Page 1
readily be adapted for various administration methods. In particular, biodegradable polymeric microparticles can provide a number of advantages over conventional parenteral formulations: Sustained delivery: By encapsulating a drug in a polymer matrix, which limits access of the biological fluid into the drug until the time of degradation, microparticles maintain the blood level of the drug within a therapeutic window for a prolonged period. Toxic side effects can be minimized, and patient compliance can be improved by reducing the frequency of administration. Local delivery: Subcutaneously or intramuscularly applied microparticles can maintain a therapeutically effective concentration at the site of action for a desirable duration. The local delivery system obviates systemic drug administration for local therapeutic effects and can reduce the related systemic side effects. This system has proven beneficial for delivery of local anesthetics. Pulsatile delivery: While burst and pulsatile release is not considered desirable for the sustained delivery application, this release pattern proves to be useful for delivery of antibiotics and vaccines. Pulsatile release of antibiotics can alleviate evolution of the bacterial resistance. In the vaccine delivery, initial burst followed by delayed release pulses can mimic an initial and boost injection, respectively 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 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. Page 2
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. 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 is 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 these characteristics often allows effectual design and development of the desired microcapsule properties. 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 Page 3
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. Coating material properties o Stabilization of core material. o Inert toward active ingredients. o Controlled release under specific conditions. o Film-forming, tasteless, stable. o Non-hygroscopic, no high viscosity, economical. o Soluble in an aqueous media or solvent, or melting. o The coating can be flexible, brittle, hard, thin etc. Examples of coating materials: Water soluble: Gelatin, Gum Arabic, Starch, Polyvinylpyrrolidone, Carboxymethylcellulose, Hydroxyethylcellulose, Methylcellulose, Arabinogalactan, Polyvinyl alcohol, Polyacrylic acid. Water insoluble 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 Techniques to manufacture microcapsules Preparation of microspheres should satisfy certain criteria: 1. The ability to incorporate reasonably high concentrations of the drug. 2. Stability of the preparation after synthesis with a clinically acceptable shelf life. 3. Controlled particle size and dispersability in aqueous vehicles for injection. 4. Release of active reagent with a good control over a wide time scale. Page 4
5. Biocompatibility with a controllable biodegradability and Susceptibility to chemical modification A-Physical methods : 1. 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. 2. Air suspension method : In the air suspension coating, the fine solid core materials are suspended by a vertical current of air and sprayed with the wall material solution. After the evaporation of the solvent, a layer of the encapsulating material is deposited onto the core material. The process can be repeated to achieve the desired film thickness. The size of the core particle for this technique is usually large Micro-encapsulation by air suspension is a technique that gives improved control and flexibility compared to pan coating Page 5
3. Vibrational nozzle : Core-Shell encapsulation or Microgranulation (matrix-encapsulation) can be done using a laminar flow through a nozzle and an additional vibration of the nozzle or the liquid. The liquid can consists of any liquids with limited viscosities (0-10,000 mpa ), e.g. solutions, emulsions, suspensions, melts etc. The process works very well for generating droplets between 100 5,000 µm applications for smaller and larger droplets are known. Nozzles heads are available from one up to several hundred thousand are available. 4. Spinning disc method Suspensions of core particles in liquid shell material are poured into a rotating disc. Due to the spinning action of the disc, the core particles become coated with the shell material. The coated particles are then cast from the edge of the disc by centrifugal force. After that the shell material is solidified by external means (usually cooling This technology is rapid, cost-effective, relatively simple and has high production efficiencies B-Physico-chemical methods : 1. Coacervation : There are two methods for coacervation, namely simple and complex processes. The mechanism of microcapsule formation for both processes is identical, except for the way in which the phase separation is carried out. Page 6
In simple coacervation: a desolvation agent is added for phase separation.whereas complex coacervation involves complexation between two oppositely charged polymers. The three basic steps in complex coacervation are: Formation of three immiscible phases. Deposition of the coating. rigidization of the coating. First step: include formation of three immiscible phases; liquid manufacturing vehicle, core material and coating material.the core material is dispersed in a solution of the coating polymer. The coating material phase, an immiscible polymer in liquid state is formed by Changing temperature of polymer solution. Addition of salt. Addition of nonsolvent. Addition of incompatible polymer to the polymer solution. Inducing polymer polymer interaction. Second step: includes deposition of liquid polymer upon the core material. Third step: the prepared microcapsules are stabilized by crosslinking, desolvation or thermal treatment. figure : 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 microdroplets of coacervate; (d) coalescence of coacervate to form continuous shell around core particles. Page 7
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, nonflammable, 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. Generally there are three steps in the impregnation : 1. This process is carried out by mixing core and shell materials in supercritical fluid at high pressure. 2. During this process supercritical fluid penetrates the shell material, causing swelling. 3. When the mixture is heated above the glass transition temperature the polymer liquefies. 4. Upon releasing the pressure, the shell material is allowed to deposit onto the active ingredient. 5. When suspensions of polymer particles in water are exposed to supercritical CO2 with the presence of additives in water, the transport of the additive into polymer particles can also be enhanced. After releasing CO2, additives can be trapped in colloidal polymer particles. Page 8