Microencapsulation : a rapidly expanding technology

About Authors:
Mortoza Rahaman
B.Pharm, BCDA College of Pharmacy & Technology (WBUT), WB
M.Pharm, Dadhichi College of Pharmacy, (BPUT), Orissa
mortozarahaman970@gmail.com

Abstract:
Novel drug delivery systems have several advantages over conventional multi dose therapy. Recent trends indicate that microparticulate drug delivery systems are especially suitable for achieving controlled or delayed release oral formulations with low risk of dose dumping, flexibility of blending to attain different release patterns as well as reproducible and short gastric residence time. The release of drug from microparticles depends on a variety of factors including the carrier used to form the microparticles and the amount of drug contained in them. Consequently, microparticulate drug delivery systems provide tremendous opportunities for designing new controlled and delayed release oral formulations, thus extending the frontier of future pharmaceutical development. One such approach is using microspheres as carriers for drugs. Microencapsulation is a process where by small discrete solid particles or small liquid droplets are surrounded and enclosed by an intact shell. Microencapsulation is used to modify and delayed drug release form pharmaceutical dosage forms. A well designed controlled drug delivery system can overcome some of the problems of conventional therapy and enhance the therapeutic efficacy of a particular drug. It is the 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. Microspheres received much attention not only for prolonged release, but also for targeting of anticancer drugs to the tumor. The intent of the paper is to highlight the potential of microencapsulation technique as a vital technique in novel drug delivery.

Reference Id: PHARMATUTOR-ART-1519

Introduction
Microencapsulation is a rapidly expanding technology. It is the process of applying relatively thin coatings to small particles of solids or droplets of liquids and dispersions. 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. Microencapsulation is  receiving considerable attention fundamentally, developmentally and commercially. The term microcapsule is defined as a spherical particle with size varying from 50nm to2mm, containing a core substance. Microspheres are in strict sense, spherical empty particles. However the terms microcapsule and microsphere are often used synonymously. Over the last 25 years numerous patents have been taken out by pharmaceutical companies for microencapsulated drugs. ⁽¹⁾

Dimensions:
At present, there is no universally accepted size range that particles must have in order to be classified as microcapsules. However, many workers classify capsules as follows (accordingto the Simon Benita)

Diameter	Type of capsule
Less than 1 micron	Nanocapsule
3 to 800 micron	Microcapsule
Larger than 1000 micron	Macrocapsule

Bakan described capsules dimensionally ranging from 10 to 5000 micron as microcapsules.⁽²⁾

REASONS FOR MICROENCAPSULATION (3)
*  The primary reason for microencapsulation is found to be either for sustained or  prolonged drug release.
*  This technique has been widely used for masking taste and odor of many drugs to improve  patient compliance.
*  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.
*  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.

Microencapsulation Techniques:

Chemical methods

INTERFACIAL POLYMERIZATION:
Interfacial polymerization features in situ polymerization of reactive monomers on the surface of a droplet or particles. Two reactive monomers (typically dichloride and diamine) are respectively dissolved in immiscible solvents and mixed to form o/w emulsion (dichloride in oil phase and diamine in water phase). The monomers diffuse to the o/w interface where they react to form a polymeric membrane. A typical example of this method is making nylon microcapsules. Nonaqueous phase (chloroform/cyclohexane) containing surfactant (e.g., sorbitan trioleate) and aqueous buffer con-taining drugs to be incorporated (enzymes or proteins), protective protein (e.g., BSA or hemoglobin) and diamine are prepared respectively. Two phases are mixed and stirred to make an w/o emulsion in an ice bath un- til the desired droplet size is reached. Another nonaqueous phase containing acid chloride is added to the emulsion for interfacial polymerization. Polymerization is quenched by addition of excess nonaqueous phase. Microcapsules are allowed to sediment and collected and then washed in saline several times to remove or-ganic solvents and byproducts.  The polymerization is initiated by water in the aqeous phase with cyanoacrylate dissolved in the oil phase.⁽⁴⁾

In-situ polymerization:
It is also known as normal polymerization. By this technique, one can produce capsules and particles in micrometer and nanometer range. Polymerization techniques of pharmaceutical interest is carried out in liquid phase and they have following types:
1. Bulk polymerization
2. Suspension polymerization
3. Emulsion polymerization
4. Micelle polymerization

Bulk polymerization:
In this, mixture of monomer and drug are heated. Initiator added to accelerate the rate of the reaction.During polymerization viscosity is maintained by temperature.The polymer so obtained may be molded or fragmented as microsphere.

Suspension polymerization:
Referred asbead polymerization or pearl polymerization .It involves heating of water insoluble monomer and drug as dispersion droplet .Drug droplet contain initiator Aqueous phase may also contain stabilizers, fillers, buffers, electrolytes, etc. Washing after completion of process.

Emulsionpolymerization:
Differs from suspension polymerization by three ways: Initiator in aqueous phase , More vigorous agitation, Surfactant present in much higher concentration. This results in altered mechanisms of polymerization:
1. Excess surfactant forms micelles and take up part of monomer cause them to swell.
2. Initiator generated radical (by heat or irradiation) start polymerization
3. As monomer consumed replaced by replaced by remaining monomer by passive diffusion.

Micelle polymerization:
Differs from emulsion polymerization in that all of monomer and drug is present in micelle produced by surfactant present in suitable concentration. Diffusion of monomer is prevent by nonsolvent properties of outer phase used. Hence no product swelling occur.⁽²⁾

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.⁽⁷⁾

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Physico-chemical methods:

Coacervation-phase separation:
Microencapsulation by coacervation phase separation is generally attributed to The National Cash Register (NCR) Corporation and the patents of B.K. Green et al. The process consists of three steps.

The pocesses is carried out in three steps:

Step 1 of the process is the formation of three immiscible chemical phases: a liquid manufacturing vehicle phase, a core material phase, and a coating phase. To form the three phases, the core material is dispersed in a solution of coating polymer,the solvent being the liquid manufacturing vehicle phase. The coating material phase, an immiscible polymer in liquid state, is formed by utilization the method of phase separation and coacervation, i.e, changing of the temperature of polymer solution, or by adding of salt, nonsolvent, or by introducing polymer-polymer interaction. 

In step 2, the deposition of the liquid polymer around the interface formed between the core material and the liquid vehicle phase. In many cases physical or chemical changes in the coating polymer solution can be induced so that phase separation of the polymer will occur. Droplets of concentrated polymer solution will form and coalesce to yield a two phase liquid-liquid system. In cases in which the coating material is an immisciblpolymer of insoluble liquid polymer it may be added directly. Also monomers can be dissolved in the liquid vehicle phase and subsequently polymerized at interface.

Step3of the process involves rigidizing the coating, usally by thermal, crosslinking, or desolvation techniques, to form a self-sustaining microcapsule.

Phase separation techniques can be classified according to the method to induce phase separation; non-solvent addition, temperature change, incompatible polymer or salt addition, and polymer-polymer interaction ⁽⁸⁾.

By thermal change:
Phase separation of the dissolved polymer occurs  in the form of immiscible liquid droplets, and if a core material is present in the  system, under proper polymer concentration, temperature and agitation conditions, the liquid polymer droplets coalesce around the dispersed core material particles, thus forming the embryonic microcapsules. As the temperature decreases, one phase becomes polymer-poor (the microencapsulation vehicle phase) and the second phase. (the coating material phase) becomes polymer-rich.

By incompatible polymer addition:
It involves liquid phase separation of a polymers coating material and microencapsulation can be accomplished by utilizing the incompatibility of dissimilar polymers existing in a common solvent.

By non-solvent addition:
A liquid that is a non-solvent for a given polymer can be added to a solution of the polymer to induce phase separation. The resulting immiscible liquid polymer can be utilized to effect  microencapsulation of an immiscible core material.

By salt addition:
There are two types of coacervation: simple and complex. Simple coacervation involves the use of only one colloid, e.g. gelatin in water, and involves removal of the associated water from around the dispersed colloid by agents with a greater affinity for water, such as various alcohols and salts. The dehydrated molecules of polymer tend to aggregate with surrounding molecules to form the coacervate.Complex coacervation involves the use of more than  one colloid. Gelatin and acacia in water are most frequently used, and the coacervation is accomplished mainly by charge neutralization of the colloids carrying opposite charges rather than by dehydration.

By polymer-polymer interaction:
The interaction of oppositely charged poly electrolytes can result in the formation of a complex having such reduce solubility that phase separation occurs. ⁽¹⁾

Polymer Encapsulation by Rapid Expansion of Supercritical Fluids:
Supercritical fluids are highly compressed gasses that possess several advantageous properties of both liquids and gases. The most widely used being supercritical carbon dioxide(CO₂), alkanes (C₂to C₄), and nitrous oxide (N₂O). A small change in temperature or pressure causes a large change in the density of supercritical fluids near the critical point. Supercritical CO2 is widely used for its low critical temperature value, in addition to its nontoxic, non flammable properties; it is also readily available, highly pure and cost-effective. This technology also applicable to prepare nanoparticles also.

The most widely used methods are as follows:

• Rapid expansion of supercritical solution (RESS)
• Gas anti-solvent (GAS)
• Particles from gas-saturated solution (PGSS)

Gas anti-solvent (GAS) process:
This process is also called supercritical fluid anti-solvent (SAS). Here, supercritical fluid is added to a solution of shell material and the active ingredients and maintained at high pressure. This leads to a volume expansion of the solution that causes super saturation such that precipitation of the solute occurs. Thus, the solute must be soluble in the liquid solvent, but should not dissolve in the mixture of solvent and supercritical fluid. On the other hand, the liquid solvent must be miscible with the supercritical fluid. This process is unsuitable for the encapsulation of water-soluble ingredients as water has low solubility in supercritical fluids. It is also possible to produce submicron particles using this method.

Particles 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 (Tg), 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.⁽¹⁰⁾

Ionotropic gelation:
Ionotropic gelation is based on the ability of polyelectrolytes to cross link in the presence of counter ions to form hydrogels. Since, the use of alginates, gellan gum, chitosan, and carboxymethyl cellulose for the encapsulation of drug and even cells, ionotropic gelation technique has been widely used for this purpose . The natural polyelectrolytes inspite, having a property of coating on the drug core and acts as release rate retardants contains certain anions on their chemical structure. These anions forms meshwork structure by combining with the polyvalent cations and induce gelation by binding mainly  to the anion blocks. The hydrogel beads are produced by dropping a drug-loaded polymeric solution into the aqueous solution of polyvalent cations. The cations diffuses into the drug-loaded polymeric drops, forming a three dimensional lattice of ionically crossed linked moiety. Biomolecules can also be loaded into these hydrogel beads under mild conditions to retain their three dimensional structure. ⁽¹¹⁾

Physico-Mechanical process:

Spray drying and congealing :
Spray drying and spray congealing methods have been used for many years as microencapsulation techniques. Because of certain similarities of the two processes, they are discussed together. 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 of the coating is effected. The principal difference between the two methods, for purpose of this discussion, 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 method however is accomplished by thermally congealing a molten coating material or b solidifying a dissolved coating introducing the coating core material mixture into a nonsolvent. Removal of the nonsolvent or solvent from the coated product is ten accomplished by sorption extraction or evaporation techniques.⁽¹²⁾

Fluidized-Bed Technology:
The liquid coating is sprayed onto the particles and the rapid evaporation helps in the formation of an outer layer on the particles. The thickness and formulations of the coating can be obtained as desired. Different types of fluid-bed coaters include top spray, bottom spray, and tangential spray.

to the fluid bed such that as the solid or porous particles move to the coating region they become encapsulated. Increased encapsulation efficiency and the prevention of cluster formation is achieved by opposing f lows of the coating materials and the particles. Dripping of the coated particles depends on the formulation of the coating material. Top spray fluid-bed coaters produce higher yields of encapsulated particles than either bottom or tangential sprays.The bottom spray is also known as “Wurster’s coater” in recognition of its development by Prof. D.E. Wurster. 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 coating material adheres to the particle surface by evaporation of the solvent or cooling of the encapsulated particle. This process is continued until the desired thickness and weight is obtained. Although it is a time consuming process, the multilayer coating procedure helps in reducing particle defects.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 placed above 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. ⁽¹⁴⁾

SOLVENT EVAPORATION/EXTRACTION :
Solvent evaporation/extraction methods have been widely used to prepare microspheres loaded with vari-ous drugs, especially hydrophobic drugs. For the encap-sulation of peptide and protein drugs, oil/water (o/w), oil/oil (o/o) and water/oil/water (w/o/w) emulsifica-tion methods have been used. Depending on the number of emulsions produced during the preparation of microspheres, solvent evaporation/extraction can be divided into two methods, single emulsion and double emulsion.

Methods
=> Single Emulsion (o/o or o/w) Methods:
In single emulsion methods, peptides/proteins are pre- sent in a dispersed phase, which is a polymer solution in organic solvent such as dichloromethane or ethyl acetate. Polylactic acid (PLA) and poly(lactide-co-glycolide) (PLGA) are the most widely used biodegradable syn-thetic polymers for sustained-release preparations. The release kinetics of active components can be controlled by changing molecular weight and/or copolymer ratio of those polymers. Drugs can be dispersed as solid parti- cles or dissolved in polymer solution. The drug solution or suspension is added into a continuous phase, which can be mineral oil (o/o) or aqueous solution (o/w) con-taining emulsifiers. Emulsification is carried out by agitation, homogenization, or sonication. Emulsifiers in the continuous phase stabilize o/o or o/w emulsions being produced. Emulsifiers such as Span 85, sorbitan sesquioleate , aluminium tristearate  have been used for o/o interface, and Carbopol 951 , methyl cellulose , polyvinyl alcohol (PVA)  have been used for o/w interface.  Organic solvent in dispersed phase is removed by solvent evaporation or by solvent extraction. In solvent evaporation process, hardening of emulsion occurs when volatile organic solvent in dispersed phase leaches into continuous phase and evaporates from continuous phase at atmospheric pressure. Using vacuum or a moderate increase in temperature can accelerate the evaporation of organic solvent. In solvent extraction process, the emulsion is transferred to a large amount of water or other quenching medium, and the extraction of organic solvent occurs faster than in solvent evaporation process. Thus, microspheres produced by solvent ex-traction process are more porous than the ones produced by solvent evaporation. The porous structure usually results in faster release of peptide/protein drugs. For long-term sustained release, solvent evaporation is preferred. The prepared microspheres are collected by centrifugation or filtration, and freeze-dried.

=> Double Emulsion (w/o/w) Methods:
In double emulsion methods, an aqueous drug solu-tion is first emulsified in a polymer-dissolved organic solvent. The w/o emulsion is then added into an aqueous phase that contains emulsifier, thereby forming w/ o/w emulsion. Then, the organic solvent is removed by extracting into external aqueous phase and evaporation. ⁽⁴⁾

MultiorificeCentrifugal extrusion:
Liquids are encapsulated using a rotating extrusionhead 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  nozzles are available. (7)

Jet break-up Processes
Processes for the production of spherical and monodisperse beads are of major interest to different industries, e.g. the pharmaceutical, chemical and food industries or in biotechnology. For such bead generation we will describe here  interesting technologies based on jet break-up principle :
* the vibration technology
* the jet-cutter technology

Vibration technology:
This technology is based on an ancient principle (Lord Rayleigh, in the late 19th century) which shown that a laminar liquid jet breaks up into equally sized droplets by a superimposed vibration. The parameters are the frequency, the velocity of the jet and the nozzle diameter. They are easily and quickly determined in the light of a stroboscope to set-up an optimal vibration which can be reset in the future, making the process highly reproducible.

To guarantee the production of uniform beads or capsules and to avoid large size distributions due to coalescence effects during the flight, the droplets pass through an electrostatic field to be charged. As a result these droplets don’t hit each other during the flight and will be spread over a larger surface of the gelation bath thus resulting in monodisperse beads. With the vibration technology it is possible to produce reproducibly capsules with equal diameter and spherical shape with a diameter within a range of 0,1 up to 3 mm.If required the process can be scaled to flow rates up to 200 l/h ; and also under sterile conditions. This is particularly interesting for cell encapsulation.

JetCutter technology:
The JetCutter is a simple technology for bead production that meets the requirement of producing monodisperse beads originating from low up to high viscous fluids with a high throughput. The fluid is pressed at high velocity out of a nozzle as a solid jet. Directly underneath the nozzle the jet is cut into cylindrical segments by a rotating cutting tool made of small wires fixed in a holder. Driven by the surface tension, the cut cylindrical segments form spherical beads.

One of the major difference with the vibration technology is that only a mechanical cut and the subsequent bead shaping driven by the surface tension are responsible for bead generation, so the viscosity of the fluid has no direct influence on the bead formation itself.Then, the JetCutter technology is capable to process fluids with viscosities up to several thousands mPa·s, i.e. viscosities somewhere between honey and tooth paste. ⁽¹⁹⁾

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 tomicroencapsulation, solid particles greater than 600 microns in size are generally considered essential for effective coating, and the process has been extensively employed for the preparation of controlled release beads.

Medicaments are usually coated onto various spherical substrates such as nonpareil sugar seeds, and then coated with protective layers of various polymers. 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.⁽³⁾

Pan coating method of microencapsulation process contains two steps:)
1. Preparation of core material
2. Coating procedure

Electrostatic encapsulation:
This method is developed at Illinois Institute of Research and technology, Chicago. Langer & Yamate49successfully encapsulated glycerin with carnauba wax using this process. The microcapsules formed are of smaller than 5 micron. Larger particles are not possible as it requires high voltage & also they lack Brownian motion. ⁽²⁾

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Coating composition:

Core materials:
The core material is the material over which coating has to be applied to serve the specific purpose (Chien 1982). Core material may be in form of solids or droplets of liquids and dispersions (Bakan 1986). The composition of core material can vary and thus furnish definite flexibility and allow effectual design and development of the desired microcapsule properties. A substance may be microencapsulated for a number of reasons. Examples may include protection of reactive material from their environment (Patel  et al. 2000), safe and convenient handling of the materials (Gutcho 1979) which are otherwise toxic or noxious, taste masking, means for controlled or modified release properties (Lin and Wu 1999) means of handling liquids as solids (Peyre  et al. 2003), preparation of free flow powders and in modification of physical properties of the drug (Alireja et al. 2005). ⁽²³⁾

Liquid Core Material Examples:
Perfumes, Solvents, Vegetable Oils, Pesticides, Dyes
Catalysts, Bleaches, Cosmetics, Insecticides, Sugars
Salts,Acids, Pigments, Fungicides, Nutrients

Solid Core Material Examples:
Dextrins , Bases ,Herbicides , Pharmaceuticals , Biocides , Minerals ⁽²⁴⁾

Coating  material:
A wide variety of coating materials are available for microencapsulation. Some patent innovative coating polymers have also been developed for some special applications particularly among the bioadhesives and mucoadhesives. However, many traditional coating materials are satisfactory for the use in the gastrointestinal tract.  They include inert polymers such as ethyl cellulose and pH sensitive ones, such as carboxylate and amino derivatives, which swell or dissolve according to the degree of cross-linking . ⁽²⁶⁾

Depending upon the method of microencapsulation employed & properties of final product needed, coatings solution may contain different additive such as film formers, plasticizers, and fillersand may be applied through different solvent system.

Coating  material properties:
1. Stabilization of core material.
2. Inert toward active ingredients.
3. Controlled release under specific conditions.
4. Film-forming, pliable, tasteless, stable.
5. Non-hygroscopic, no high viscosity, economical.
6. Soluble in an aqueous media or solvent, or melting.
7. The coating can be flexible, brittle, hard, thin etc. ⁽²⁾

Coating polymers:
1.  Vegetable Gums: such as, gum Arabic, agar, sodium alginate, and carrageenan and dextran sulphate.

2.  Celluloses: such as, ethyl cellulose, nitrocellulose, carboxy methylcellulose, cellulose acetate phthalate and cellulose acetate butyrated phthalate.

3.  Condensation polymers: such as nylon, Teflon, polymethane, polycarbonate, amino resins, alkyl resins and silicone resins.

4.  Homopolymer: such as, poly vinyl chloride, polyethylene, polystyrene, poly vinyl acetate and poly vinyl alcohol.

5.  Copolymers: such as maleic anhydride copolymer with ethylene or vinyl methyl ether, acrylic  acid copolymers and methacrylic acid co-polymers (eudragit).

6.  Proteins: such as collagen, gelatin, casein, fibrinogen, hemoglobin and poly amino acids. Waxes: such as wax, paraffin, rosin (Pathak, Nikore and Dorle 1985), shellac, tristerium, monoglyceride, bees wax, oils, fats and hardened oils.

7.  Curable polymers: such as, epoxy resins, nitro paraffin and nitrated polystyrene. ⁽²⁸⁾

Mechanism and kinetics of drug release :

KINETICS OF DRUG RELEASE:
Release of the active constituent is an important consideration in case of microcapsules.Many therotically possible mechanisms may be considered for the release of the drug from the microparticulates.
1.  Liberation due to polymer erosion or degradation
2.  Self diffusion through the pore
3.  Release from the surface of the polymer.
4.  Pulsed delivery initiated by the application of an oscillating or sonic field.

In most of the cases, a combination of more than one mechanism for drug release may operate, so the distinction amongst the mechanisms is not always trivial. The release profile from the microcapsules depends on the nature of the polymer used in the preparation as well as on the nature of the active drug. Attempts to model drug release from microcapsule have been reported and in the treatment of their data, it was assumed that drug release was confined to any of the order such as zero order or first order processes. One indication of mechanism can be obtained using a plot of log of cumulative percentage of drug remaining in the matrix against time. First order release would be linear as predicted by following equation.

Log C      = Log Co - Kt /2.303 ———-—————(1)

C = Amount of drug left in the matrix
Co = Initial amount of drug in the matrix
K = First order rate constant, (time ^–1)
t = time, either in hours or minutes

The  in-vitro drug release data obtained from selected batch of  microcapsules was treated according to equation (1) by plotting log of cumulative % of drug remaining against time. Next, an attempt was made to see whether the drug release is by diffusion. For system, which will release the drug by diffusion, were proposed by Higuchi………..

Q   = [D ε/ τ (2A – ε Cs) Cs t]^{1/2 ………………………………….(2)}

Q = Weight in grams of drug released per unit surface area.
D = Diffusion co-efficient of drug in the release medium.
ε = Porosity of the matrix.
Cs = Solubility of drug in the microcapsule expressed as gm/ml.
A = Total concentration of drug in matrix
τ =Tortuosity of the matrix
t = Time

The assumption made in the deriving equation (2) is as follows:
=>  A pseudo steady state is maintained during release.
=>  A » Cs i.e., excess solute is present.
=> C = 0 solution at all times (perfect sink). (Dr K.R.Patel* et al. /International Journal Of Pharmacy&Technology )
=>  Drug particles are much smaller than those in the matrix.
=>  The diffusion coefficient remains constant.
=>  No interaction between the drug and the matrix occurs.

For the purpose of data treatment, equation is usually reduced to,

Q = Kt^1/2 ---------------(3)

Therefore a plot of amount of drug released verses the square root of time should be linear if the drug release from the matrix is diffusion controlled.

Precisely, to know the exact mechanism of drug release, whether it is by diffusion or with combination of diffusion and erosion control, the data has also been plotted according to equation as suggested by Korsemeyer they used a simple empirical equation to describe the general solute release behavior from control release polymer matrices.

Mt / M∞  = Ktⁿ ....         --------------------  (4)

Mt / M∞  = fraction of drug release
K = Kinetic rate constant
t = Release time.
n = Diffusional exponent for drug release.

The value of 'n' gives an indication of the release mechanism. For non –Fickian release, the ‘n’ value falls between 0.5 and 1.0, while in the case of Fickian diffusion,  n ≤ 0.5 for zero order release (case II transport) n = 1 and for super case II transport  n > 1.

The in-vitro drug release data obtained from microcapsules was treated according to equation (4) by plotting log cumulative percentage of drug release Vs log  time.   =  the fraction of drug release.⁽¹⁾

Diffusion:
Diffusion is the most commonly involved mechanism wherein the dissolution fluid penetrates the shell, dissolves the core and leak M.N. Singh et al. / RPS 2010; 5(2): 65-77 70out 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 Higuchi’s equation as below :

Q   = [D ε/ τ (2A – ε Cs) Cs t]^1/2

Q = Weight in grams of drug released per unit surface area.
D = Diffusion co-efficient of drug in the release medium.
ε = Porosity of the matrix.
Cs = Solubility of drug in the microcapsule expressed as gm/ml.
A = Total concentration of drug in matrix
τ =Tortuosity of the matrix
t = Time

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 glyceryl monostearate, bee’s wax and stearyl alcohol .  Attempts 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. However, based on various studies concerning the release characteristics, the following generalizations can be made:
1.Drug release rate from microcapsules conforming to reservoir type is of zero order.

2. Microcapsules of monolithic type and containing dissolved drug have release rates that are t^1/2 dependant for the first half of the total drug release and thereafter decline exponentially.

3. However, if a monolithic microcapsule containing large excess of dissolved drug, the release rate is essentially t^1/2 dependant throughout almost the entire drug release.  In monolithic capsules the path traveled by drug is not constant; the drug at the center travels a large distance than the drug at the surface. Therefore, the release rate generally decreases with time. ⁽³⁰⁾

Physicochemical Evaluations:
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.

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.

Polymer solubility in solvent:
Solution turbidity is a strong indication of solvent power. The cloud point can be used for the determination of the solubility of the polymer in different organic solvents.

Viscosity of polymer solution:
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.

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.

Bulk density:
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.

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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 20ºC within a minute of deposition of microspheres .

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. ⁽³¹⁾

Particle size measurement:
The size of the prepared microcapsules are measured by the optical microscopy method using a calibrated stage micrometer. Particle size is calculated by using equation,  Xg = 10 x [(ni x log Xi) / N], Where,  Xg is geometric mean diameter, ni is number of particle in range, Xi is the mid point of range and N is the total number of particles.

Flow properties of microcapsules:
Flowability of microcapsules is investigated by determining Angle of repose, bulk density, Carr’s index and Hausner ratio. The angle of repose is determined by fixed funnel method. The microcapsules are tapped using bulk density apparatus (Excel Enterprises, Kolkata) for 1000 taps in a cylinder and the change in volume are measured. Carr index and Hausner ratio are calculated by the formula,

Carr index (%) = (Df-D0) ×100  ⁄ Df  and
Hausner ratio = Df  ⁄D0, where, Df is poured density; D0 is tapped density.

Drug entrapment efficiency (DEE):
Drug loaded microcapsules (100 mg) are powdered and suspended in 100 ml water solvent system. The resultant dispersion is kept for 30 min for complete mixing with continuous agitation and filtered through a 0.45 µm membrane filter. The drug content is determined spectrophotometrically (UV-Visible-1700, Shimadzu, Japan spectrophotometer) by the equation, DEE = (Pc / Tc) X 100, Where, Pc is practical content, Tc is the theoretical content.

Scanning Electron Microscopy (SEM):
The SEM analysis is carried out using a scanning electron microscope (LEO, 435 VP, U.K.). Prior to examination, samples are mounted on an aluminium stub using a double sided adhesive tape and making it electrically conductive by coating with a thin layer of gold (approximately 20 nm) in vacuum.

Percentage moisture loss:
The microcapsules are evaluated for percentage moisture loss which sharing an idea about its hydrophilic nature.  The microcapsules  weighed (W₁) initially kept in desiccator containing calcium chloride at 37°C for 24 hours. The final weight  (W₂) was noted when no further change in weight of sample is observed.

Moisture loss = [(W₁ – W₂)/ W₂] X 100.

Determination of swelling properties:
Microcapsules of known weight were placed in dissolution solution for 6 hr and the swollen microcapsules were collected by a centrifuge and the wet weight of the swollen microcapsules was determined by first blotting the particles with filter paper to remove absorbed water on surface and then weighing immediately on an electronic balance. The percentage of swelling of microcapsules in the dissolution media was   115 then calculated by using equation, Sw = [(Wt-Wo)/Wo] ×100,  where, Sw= percentage of swelling of microcapsules, Wt = weight of the microcapsules at time t, Wo = initial weight of the microcapsules.

Determination of wall thickness:
Wall thickness of microcapsules was determined by method of Luu et al using equation,  h = [r (1-P) d₁/3{Pd₂+ (1-P) d₁}] × 100, where, h= wall thickness, r = arithmetic mean radius of microcapsules, d₁ and d₂ are densities of core and coat material respectively, P is the proportion of medicament in microcapsules.. ⁽³²⁾

In-vitro release studies:
Release studies for microcapsules can be carried out in different pH condition like pH 1.2 and pH 7.4 using USP rotating basket or paddle apparatus. The samples are taken at specific time intervals and are replaced by same amount of fresh medium. The samples withdrawn are analyzed as per the monograph requirement and release profile is determined using the plot of amount released as a function of time. ⁽³³⁾

Pharmaceutical Application(34)
*    Oral
*    Injectables
*    Nasal
*    Ocular
*    Otic
*    Transdermal
*    Targeted delivery
*    Lower dose requirements
*    Fewer systemic side effects
*    Improved bioavailability
*    Taste masking
*    Improve drug stability
*    Alternative formulations
*    Potent drug
*    Controlled substances

Conclusion
Microparticulate drug delivery systems provide tremendous opportunities for designing new controlled and delayed release oral formulations, thus extending the frontier of future pharmaceutical development. The Microparticulate offers a variety of opportunities such as protection and masking, reduced dissolution rate, facilitation of handling, and spatial targeting of the active ingredient. 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 vario