MICROENCAPSULATION

Definition:It is the process by which individual particles or droplets of solid or liquid material (the core) are surrounded or coated with a continuous film of polymeric material (the shell) to produce capsules in the micrometer to millimeter range, known as microcapsules.

OrMicroencapsulation may be defined as the process of surrounding or enveloping one substance within another substance on a very small scale, yielding capsules ranging from less than one micron to several hundred microns in size.

Features of Microcapsule:Microencapsulation is the packaging of small droplets of liquid or particles with a thin film.

Size:Typically, the lowest particle size of microcapsules is 1m and the largest size is 1mm.

Composition:Microcapsules consist of a core and a wall (or shell).

Shape:The configuration of the core can be a spherical or irregular particle, liquid-phase suspended solid, solid matrix, dispersed solid and aggregates of solids or liquid forms.

Classification:Microcapsules can be classified on three basic categories according to their morphology as follows,1. Mononuclear:Mononuclear (core-shell) microcapsules contain the shell around the core.2. Polynuclear:Polynuclear capsules have many cores enclosed within the shell.3. Matrix types:In matrix encapsulation, the core material is distributed homogeneously into the shell material.

In addition to these three basic morphologies, microcapsules can also be mononuclear with multiple shells, or they may form clusters of microcapsules.

Generally microparticles are divided in to two components;a) Core material.b) Coat or wall or shell material.

Core materials:The material to be coated. It may be liquid or solid or gas. Liquid core may be dissolved or dispersed material.

Composition of core material:

Drug or active constituent.

Coating materials:

Gums: Gum arabic, sodium alginate, carageenan. Carbohydrates: Starch, dextran, sucrose Celluloses: Carboxymethylcellulose, methycellulose. Lipids: Bees wax, stearic acid, phospholipids. Proteins: Gelatin, albumin.

REASONS FOR ENCAPSULATION:

This technique has been widely used for masking the organoleptic properties like taste and odor of many drugs and thus improves patient compliance e.g. Paracetamol, nitrofurantoine for masking the bitter taste. By using microencapsulation techniques the liquid drugs can be converted in a free flowing powder. The drugs can be protected by microencapsulation which is sensitive to moisture light and oxygen, such as nifedipine is protected from photo instability. Microencapsulation technique also helpful to prevent the incompatibility between drugs The drugs which are volatile in nature may vaporize at room temperature like Aspirin and peppermint oil can be prevented by microencapsulation.

Microencapsulation has also been employed to change the site of absorption. This application has been useful for those drugs which have the toxicity at lower pH.

1. Core protection:The core must be isolated from its surroundings, as1. 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,

2. Controlled release of drug:1. For targeted drug delivery2. For delayed release of drug3. For prolong release of drug4. To increase bioavailability of drug

TECHNIQUES TO PREPARE:

These depends on

1.0 DRUG FACTORS:

Physical properties Chemical properties Biological activity Nature of drug Stability of drug

2.0 PRODUCTION REQUIREMENT:

Entrapment efficiency Percentage yield

PHYSICAL METHODS

Spray drying Spray congealing Air suspension Fluid bed coating Pan coating Centrifugal extrusion Vibration nozzle Multi orifice centrifugation process Spinning disk

SPRAY DRYING AND SPRAY CONGEALINGSPRAY DRYING:Microencapsulation by spray-drying is a low-cost commercial process which is mostly used for the encapsulation of fragrances, oils and flavors.Steps:1. Core particles are dispersed in a polymer solution and sprayed into a hot chamber.1. The shell material solidifies onto the core particles as the solvent evaporates.The microcapsules obtained are of polynuclear or matrix type.

SPRAY-CONGEALING:- This technique can be accomplished with spray drying equipment when the protective coating is applied as a melt.

1- The core material is dispersed in a coating material melt.2- Coating solidification (and microencapsulation) is accomplished by spraying the hot mixture into a cool air stream.- e.g. microencapsulation of vitamins with digestible waxes for taste masking.

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 airstream.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.

FLUID BED COATINGFluid bed coating is restricted to encapsulation of solid core materials, including liquids absorbed into porous solids. Solid particles to be encapsulated are suspended on a jet of air and then covered by a spray of liquid coating material. The capsules are then moved to an area where their shells are solidified by cooling or solvent vaporization. The process of suspending, spraying, and cooling is repeated until the capsules' walls are of the desired thickness.

Different types of fluid-bed coaters include top spray, bottom spray, and tangential spray(a) Top spray(b) Bottom spray(c) Tangential spray.In the top spray system the coating material is sprayed downwards on to the fluid bed such that as the solid or porous particles move to the coating region they become encapsulated. The bottom spray is also known as Wursters coater. This technique uses a coating chamber that has a cylindrical nozzle and a perforated bottom plate. The cylindrical nozzle is used for spraying the coating material. As the particles move upwards through the perforated bottom plate and pass the nozzle area, they are encapsulated by the coating material.The tangential spray consists of a rotating disc at the bottom of the coating chamber, with the same diameter as the chamber. During the process the disc is raised to create a gap between the edge of the chamber and the disc. The tangential nozzle is placedAbove the rotating disc through which the coating material is released. The particles move through the gap into the spraying zone and are encapsulated. As they travel a minimum distance there is a higher yield of encapsulated particles.

SPINNING DISK

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, and relatively simple and has high production efficiencies.

PAN COATING

When coating is liquid?

Coating is applied as a coating solution or atomized spray to the dried solid core particles in the coating pan. To remove the coating solvent warm air is supplied to the coated materials while coatings are applied in the coating pan.On some cases the solvent is removed by drying in the oven.

When coating is solid?

1- Solid particles are mixed with a dry coating material. 2- The temperature is raised so that the coating material melts and encloses the core particles, and then is solidified by cooling.

CENTRIFUGAL EXTRUSIONAs shown in Figure The simple extrusion method utnizes a device consisting of two concentric tubes containing aligned fluid nozzles. The liquid material to be coated is extruded through the nozzle of the inner tube into the coating fluid contained in the outer tube. Initially. The fluid extrudes as a rod surrounded by the coating fluid, but the rod ultimately breaks up into droplets which are then immersed in the coating fluid. As the extruded droplets pass through the nozzle orifice of the outer tube. The coating fluid forms a surface coat which encases the extruded particle.

Spherically shaped particles are formed by the surface tension of the liquid. By suitable means the formed coat is converted to a more rigid structure. Hardening baths are usually employed for this purpose.

VIBRATIONAL NOZZLE:It works under the same principle as the extrusion only difference is that an additional vibrational nozzle is used for encapsulation and flow of fluid is laminar.Matrix-encapsulation can be done using a laminar flow through a nozzle and an additional vibration of the nozzle or the liquid.

MULTI ORIFICE-CENTRIFUGAL PROCESS: Microencapsulation by the multi orifice-centrifugal process is the mechanical process in which the centrifugal force is applied to throw a core material particle through an enveloping microencapsulation membrane.

The factors affect the Process include the rotational speed of the cylinder, the flow rate of the coating and core materials and the concentration, viscosity and surface tension of the core material. It consists of a cylinder containing three circumferential grooves (coating material inlet)Core material inletCounter rotating discRotating cylinder

Process: Coating material is introduced through the inlet grooves. The coating material under the influence of centifugational force imparted by cylinder rotation flows outward along the immediate groove and form film on orifice. The counter rotating disc disperses the core material towards the orifice. Core material encounters the coating material membrane at orifice and encapsulation occurs.

CHEMICAL METHODS

1. SOLVENT EVAPORATION METHOD

Process Step I (Dispersion of Drug in Polymer Solution)In this process microcapsule coating (polymer) is dissolved in a volatile solvent, which is immiscible with the liquid manufacturing vehicle phase.Methylene chloride is a preferred solvent because of its high volatility (boiling point 41C). Mixed solvents can also be used. The mixtures used so far tend to contain a water-immiscible solvent (e.g., CH2CI2) and a water-miscible solvent (e.g., acetone). The water immiscible solvent is the predominant component of the mixture. Once the desired coating polymer is dissolved in the organic solvent, the drug to be encapsulated is added to this solution. The drug agent may be a solid (crystalline or amorphous) or a nonvolatile liquid. The added drug may completely dissolve in the polymer solution or it may be completely insoluble and simply form a dispersion, suspension, or suspension-emulsion.

Step II (Emulsification)To obtain the microcapsule of appropriate size the core and coating material mixture is dispersed in the liquid manufacturing vehicle phase (water) with agitation.The drug/polymer/solvent mixture (i.e., the oil phase) is emulsified in water to form an oil-in-water emulsion. In order to aid emulsification, a surfactant (PVA) is normally dissolved in the water phase before the oil-in-water emulsion is formed. Step III (Evaporation)Evaporation is carried out by heating. Step IV (Separation)Once solvent evaporation appears to be complete, the capsules are separated from the suspending medium by filtration, washed, and dried.

If the core material is dispersed in the polymer solution the polymer shrinks around the core. And if core material is dissolved in the coating solution matrix type microcapsules are formed.

POLYMERIZATION:

Microencapsulation by polymerization involved reaction of monomeric units located at interface between a core material substance and continuous phase in which the core material is dispersed. In polymerization a liquid or gaseous phase is used as continuous or core material and as a result the polymerization reaction occurs at a liquid-liquid, solid-liquid, Liquid-gas, or solid-gas interface.

1. Interfacial polymerization (IFP)In this technique the capsule shell will be formed 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 Multifunctional acid chlorides These will be used either individually or in combination.Process The multifunctional monomer (acid chlorides immiscible with water) dissolved in liquid core material and it will be dispersed in aqueous phase containing dispersing agent. A co reactant multifunctional amine will be added to the mixture. The polymerization depends on the fact that acid halides are water insoluble and diamines have partition coefficient toward the water immiscible organic phase and diffuse towards it and it results in rapid polymerization at interface and generation of capsule shell takes place. A poly urea shell will be formed when isocyanate reacts with amine A polynylon or polyamide shell will be formed when acid chloride reacts with amine.

2. In situ polymerization (ISP)In this process no reactive agents are added to the core material, polymerization occurs exclusively in the continuous phase. Initially a low molecular weight pre polymer will be formed, as time goes on the pre polymer grows in size, it deposits on the surface of the dispersed core material there by generating a solid capsule shell.

3.0 PHYSICOCHEMICAL METHOD:

COESERVATIONA coacervate is a tiny spherical droplet of assorted organic molecules (specifically, lipid molecules) which is held together by hydrophobic forces from a surrounding liquid. Their name derives from the Latin coacervare, meaning to assemble together or cluster.

PROCESSThe general outline of the processes consists of three steps carried under continuous agitation:Step 1: Formation of three immiscible chemical phasesThe immiscible chemical phases are (i) A liquid manufacturing vehicle phase (ii) A core material phase (iii) A coating material phaseTo form the three phases, the core material is 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 phase separation coacervation, that is, By changing the temperature of the polymer solution By adding incompatible polymer to the polymer solution By inducing a polymer-polymer interaction

Step 2: Depositing the liquid polymer coating upon the core materialThis is accomplished by controlled, physical mixing of the coating material (while liquid) and the core material in the manufacturing vehicle. Deposition of the liquid polymer coating around the 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 coalescence of the liquid polymer droplets.Step 3: Rigidizing the coatingThis is usually done by Thermal Technique Cross linking Technique Desolvation Technique, to form a self-sustaining microcapsule.

1. TEMPERATURE CHANGE METHOD:Change in temperature causes separation of coating material from the solventUseful when the solubility of the material depend on temperature E.g. Coating mat.: Ethyl cellulose in cyclohexane (EC is insoluble in Cyclohexane at room temp.) Core Material: N-Acetyl P-Amino PhenolThe EC is insoluble in cyclohexane at room temperature but is soluble at elevated temperatures. The mixture is heated to the boiling point to form a homogeneous polymer solution. The finely divided core material is dispersed in the solution with stirring. Allowing the mixture to cool with continued stirring, and microencapsulation of the core material occurs.2. INCOMPATIBLE POLYMER ADDITION:The polymer which is chemically not compatible will be added to the coating solutionThe polymer which is to be added should have More affinity towards solvents No interaction with the core material.E.g: Addition of liq. Polybutadiene(Incompatible polymer) to the EC solution in toluene (Coating sol.). Core material: Methylene blue HCl.Dissolves EC in toluene disperse methylene blue with stirring slowly add liqpolybutadiene solidification by addition of hexane filtration and drying of microcapsules.3. SALT ADDITION: Soluble inorganic salts can be added to aqueous solutions of certain polymers Should be soluble in water Should precipitate the polymer from the solution.Eg: Addition of 20% Sod. Sulfate to the gelatin solution.Core Mat.: Oil soluble vitamin in corn oil.4. NON-SOLVENT ADDITIONPhase separation can be induced by addition of non-solvent for given polymer.Have more affinity towards solvent which is usedPrecipitate the coating polymer Eg: Addition of Isopropyl ether to Cellulose acetate butyrate (CAB) dissolved in Methyl ethyl ketone. Core Mat: Methyl Scopolamine HBrsolution of CAB in MEK Add micronized methylscopolamine with stirring heat 55 C slowly add isopropyl ether slowly cool to room tempertaure5. POLYMER- POLYMER INTERACTION (COMPLEX COACERVATION): Core material Eg: gelatin below its isoelectric pH possess + ve charge, acacia is vely charged. Core mat: Methyl Salicylate.Both polymers show attraction due to opposite charge and form coacervate, which is the deposited around the core due by stirring.Coacervation types on polymer solution:1) Aqueous phase separation:Core material hydrophobicCote material hydrophilic

Simple coacervation Water-immiscible liquidaqueous coating solutionOR (gelatin in water) Water-insoluble solids

O/W emulsion (or)aqueous suspension of solid particleThen add slowly 20% sod.sulphate solution with continuous stirring

Gel the colloid by pouring coacervate mixture in to 7% w/w sod.sulphate solution

Filter and wash coacervate with cold water and remove salt

Treat filtered material with formaldehyde to harden the coacervate

Filter and wash Particles with cold water to remove hardening agent

Dry to remove remaining solventa) Complex coacervation:Water-immiscible liquidaqueous coating solutionOR (acacia in water) Water-insoluble solids

O/W emulsion (or)Aqueous suspension of solid particles

Add gelatin solution with stirring

Add warm water until coacervate is produced

Add coacervate mixture in cold water

Treat filtered material with formaldehyde to harden the coacervate

Filter and wash Particles with cold water to remove hardening agent.

Dry to remove remaining solvent

2) Organic phase separation:This method is opposite to aqueous phase separation.Core material hydrophilicCote material hydrophobic

Water-miscible liquidpolymer in organic solvent ORWater-soluble solids

W/O emulsion (or)Suspension of solid particles (in organic solvent)

Addition of non-solvent for polymer (mineral oil)

Phase separation (microcapsules are produced)

Cooling of microcapsules to solidify coating

Filter wash and dry5. POLYMER ENCAPSULATION BY RAPID EXPANSION OF SUPERCRITICAL FLUIDSSupercritical fluids are highly compressed gasses. Properties Possess properties of both liquids and gases Miscible with common gases such as hydrogen (H2) and nitrogenCommonly Used Agents Supercritical CO2 Alkanes (C2 to C4) Nitrous oxide (N2O) Supercritical CO2 is widely used for its following properties: -Properties Nontoxic Nonflammable Readily available Highly pure Cost-effectiveApplications It has found applications in encapsulating active ingredients by polymers.Core Materials Different core materials such as pesticides, pharmaceutical ingredients, vitamins, and dyes are encapsulated using this method.Shell Materials A wide variety of shell materials that either dissolve (acrylates, polyethylene glycol) or do not dissolve (proteins, polysaccharides) in supercritical CO2 are used for encapsulating core substances.MethodsThe most widely used methods are as follows: Rapid expansion of supercritical solution (RESS) Gas anti-solvent (GAS) Particles from gas-saturated solution (PGSS)I Rapid expansion of supercritical solution (RESS)In this process, supercritical fluid containing the active ingredient and the shell material are maintained at high pressure and then released at atmospheric pressure through a small nozzle. The sudden drop in pressure causes desolvation of the shell material, which is then deposited around the active ingredient (core) and forms a coating layer.Disadvantage The disadvantage of this process is that both the active ingredient and the shell material must be very soluble in supercritical fluids. The solubility of polymers can be enhanced by using co-solvents and non-solvents.Example Microencapsulation of TiO2 nanoparticles with polymer by RESS using ethanol as a non-solvent for the polymer shell such as polyethylene glycol (PEG), and polymethyl methacrylate

A schematic of the microencapsulation process using supercritical CO2

II GAS ANTI-SOLVENT (GAS) PROCESSThis process is also called supercritical fluid anti-solvent (SAS). Here, supercritical fluid is added to a solution of shell material andthe active ingredients and maintained at high pressure. This leads to a volume expansion of the solution that causes super saturationsuch that precipitation of the solute occurs. Thus, the solute must be soluble in the liquid solvent, but should not dissolve in themixture of solvent and supercritical fluid. On the other hand, the liquid solvent must be miscible with the supercritical fluid.Advantage It is alsopossible to produce submicron particles using this method. Disadvantage This process is unsuitable for the encapsulation of water-soluble ingredients as water has low solubility in supercritical fluids.IIIPARTICLES FROM A GAS-SATURATED SOLUTION (PGSS)This process is carried out by mixing core and shell materials in supercritical fluid at high pressure. During this process supercritical fluid penetrates the shell material, causing swelling. When the mixture is heated above the glass transition temperature the polymer liquefies. Upon releasing the pressure, the shell material is allowed to deposit onto the active ingredient. In this process, the core and shell materials may not be soluble in the supercritical fluid.

MECHANISMS AND KINETICS OF DRUG RELEASE

Major mechanisms of drug release from microcapsules include diffusion, dissolution, osmosis and erosion.Diffusion: Diffusion is the most commonly involved mechanism wherein the dissolution fluid penetrates the shell, dissolves the core and leak out through the interstitial channels or pores. Thus, the overall release depends on, (a) the rate at which dissolution fluid penetrates the wall of microcapsules, (b) the rate at which drug dissolves in the dissolution fluid, and (c) the rate at which the dissolved drug leak out and disperse from the surface. The kinetics of such drug release obeys Higuchis equation as below: Q =[D/J(2A-CS)CSt]1/2Where, Q is the amount of drug released per unit area of exposed surface in time t; D is the diffusion coefficient of the solute in the solution; A is the total amount of drug per unit volume; CS is the solubility of drug in permeating dissolution fluid; is the porosity of the wall of microcapsule; J is the tortuosity of the capillary system in the wall. The above equation can be simplified to Q = vt where, v is the apparent release rate.Dissolution: Dissolution rate of polymer coat determines the release rate of drug from the microcapsule when the coat is soluble in the dissolution fluid. Thickness of coat and its solubility in the dissolution fluid influence the release rate.Osmosis:The polymer coat of microcapsule acts as semi permeable membrane and allows the creation of an osmotic pressure difference between the inside and the outside of the microcapsule and drives drug solution out of the microcapsule through small pores in the coat.Erosion: Erosion of coat due to pH and/or enzymatic hydrolysis causes drug release with certain coat materials like glycerylmonostearate, bees wax and stearyl alcohol.11Attempts to model drug release from microcapsules have become complicated due to great diversity in physical forms of microcapsules with regard to size, shape and arrangement of the core and coat materials. The physiochemical properties of core materials such as solubility, diffusibility and partition coefficient, and of coating materials such as variable thickness, porosity, and inertness also makes modeling of drug release difficult.

Loading Of Drug In Microsphere:Mechanisms For Loading Drug:Drug can be loaded by a. physical entrapment b. chemical linkagec. surface adsorption The active components are loaded over the microsphere principally at two points a. During the preparation of microsphere b. After the formation of microsphere by incubating them with the drug or protein. MAXIMUM LOADING can be achieved by incorporating drug during the time of preperation.Loading during preparation is avoided because during prep loading is effected by 1) Method of preparation.2) Presence of additives e.g. crosslinking agent, surfactant stabilizer.3) Heat of polymerization.4) Agitation intensity.KINETICS OF DRUG RELEASE:

In some cases, the release rateis zero-order, i.e. the release rate is constant. In this case, the microcapsules deliver a fixed amount of drug per minute or hour during the period of their effectiveness. This can occur as long as a solid reservoir or dissolving drug is maintained in the microcapsule.A more typical release pattern is first-order in which the rate decreases exponentially with time until the drug source is exhausted. In this situation, a fixed amount of drug is in solution inside the microcapsule. The concentration difference between the inside and the outside of the capsule decreases continually as the drug diffuses.

APPLICATIONS OF MICROENCAPSULATION(A) PHARMACEUTICAL APPLICATIONS:(1) CONTROLLED DRUG RELEASE:Many varieties of both oral and injectable pharmaceutical formulations are microencapsulated to release the drug over longer period of time. Aspirin controlled release version Zorprin CR tablet that is used for arthritis. Niaspan CR tablets that is used for lowering cholesterol levels and it reduces the risk of heart attack.

(2) TARGETTED DRUG RELEASE:Certain anti-tumor drugs are microencapsulated for targeted drug delivery.Alginate-Poly-L-Lysine-Alginate microcapsules of anti-tumor drugs are mostly used and they bind to tumor antigen TAG72.

(3) RECOMBINANT GENE THERAPY:Corrective gene sequence in the form of plasmids are microencapsulated to be incorporated in the body for the treatment of genetic disorders.

(4) ENZYME AND MICROBES IMMOBILIZATION:Enzymes have been encapsulated in cheese to accelerate ripening and flavor development. The encapsulated enzymes are protected from low pH and high ionic strength in cheese.Encapsulation of microbes has been used to improve stability of starter culture.

(5) IMPROVED SHELF LIFE:Microencapsulation of drugs enhances their shelf life by preventing degradative reactions (dehydration and oxidation).

(6) PROTECTION AGAINST ENVIRONMENTAL EFFECTS:Microencapsulation protects the drugs against environmental effects of UV rays, heat, oxidation, acids and bases. E.g: microencapsulation of vitamin A palmitate and vitamin K.

(7) MASKING OF BITTER TASTE AND ODOUR:Microencapsulation masks the bitter taste of drugs like paracetamol and nitrofurantoin etc.It also decreases the odour and volatility of certain compounds like carbon tetrachloride (CTC).

(8) IMPROVED PROCESSING, TEXTURE AND LESS WASTAGE OF INGREDIENTS: Control of hygroscopy (NaCl) Enhanced flowability and dispersibilityMicroencapsulation of non-flowing multicomponent solid mixture of thiamine, riboflavin, niacin and iron phosphate for easy tableting. Enhanced solubility

(9) MIXING OF INCOMPATIBLE COMPOUNDS:Microencapsulation allows mixing of incompatible compounds like for easy addition of oily ingredients in formulations.

(10) MICROENCAPSULATION OF INSULINE AND PANCREATIC ISLETS: For better and prolonged therapeutic effects of insulin. For the improvement of compromised pancreatic function.