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 [1,2].

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 proteins or synthetic polymers which are biodegradable in nature and ideally having particle size less than 200μm. 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 Bio encapsulation 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 [3,4].

Microencapsulation can be done

i. To protect the sensitive substances from the external environment,

ii. To mask the organoleptic properties like colour, taste, odour of the substance,

iii. To obtain controlled release of the drug substance, (iv) for safe handling of the toxic materials,

iv. To get targeted release of the drug and

v. To avoid adverse effects like gastric irritation of the drug, e.g. aspirin is the first drug which is used to avoid gastric irritation. Microparticles or microcapsules consist of two components, namely core material and coat or shell material. Core material contains an active ingredient while coat or shell material covers or protects the core material. Different types of materials like active pharmaceutical ingredients, proteins, peptides, volatile oils, food materials, pigments, dyes, monomers, catalysts, pesticides, etc. can be encapsulated with different types of coat or shell materials like ethylcellulose, hydroxyl propylmethyl cellulose, sodium carboxy methyl cellulose, sodium alginate, PLGA, gelatine, polyesters, chitosans, etc.

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.

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.

· 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.

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

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 [5,6].

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. [7-9].

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 these characteristics often allows effectual design and development of the desired microcapsule properties [10].

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 [11]. 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.

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 [12].

The selection of a given coating often can be aided by the review of existing literature and by the study of free or cast films, although practical use of free-film information often is impeded for the following reasons:

· 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 [13].

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.

Examples of coating materials:

Water soluble resins:

Gelatin, Gum Arabic, Starch, Polyvinylpyrrolidone, Carboxymethyl cellulose, Hydroxyethyl cellulose, 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 [14].

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 [15].

Microencapsulation techniques:

Various techniques are available for the encapsulation of core materials. Broadly the methods are divided into three types. Different types of microencapsulation techniques

1 Chemical methods;

2 Physico-chemical methods; and

3 Physico-mechanical methods.

The above-mentioned techniques are widely used for microencapsulation of several pharmaceuticals. Among these techniques, fluidized bed or air suspension method, coacervation and phase separation, spray drying and spray-congealing, pan coating and solvent evaporation methods are widely used. Depending on the physical nature of the core substance to be encapsulated the technique used will be varied. [16]

Interfacial polymerization (IFP):

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 co-reactant multifunctional amine will be added to the mixture. This results in rapid polymerization at interface and generation of capsule shell takes place (Scher 1983). 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 it produces a polyurethane shell. For example, Saihi et al. (2006) encapsulated di-ammonium hydrogen phosphate (DAHP) by polyurethane-urea membrane using an interfacial polymerization method. An elevated yield of synthesis (22%) of a powder of microcapsules was produced with a fill content of 62 wt % of DAHP as determined by elementary analysis. The mean size of DAHP microcapsules is 13.35 mm. Besides, 95% of the sized particles have a diameter lower than 30.1 mm. [17]

In situ polymerization:

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 a solid capsule shell (e.g. encapsulation of various water-immiscible liquids with shells formed by the reaction at acidic pH of urea with formaldehyde in aqueous media (Cakhshaee et al. 1985)). Wang et al. (2003) prepared Carboxyl-functionalized magnetic microspheres by in situ polymerization of styrene and methyacrylic acid at 85_C in the presence of nano-Fe3O4 in styrene, using lauroyl peroxide as an initiator.[18]

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 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.

Coacervation and phase separation. Bungenberg de Jong and Kruyt (1929) and Bungenberg de Jong (1949) defined this as partial desolvation of a homogeneous polymer solution into a polymer-rich phase (coacervate) and the poor polymer phase (coacervation medium). The term originated from the Latin ‘acervus’ meaning ‘heap’. This was the first reported process to be adapted for the industrial production of microcapsules. Currently, two methods for coacervation are available, 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. 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; and

· Rigidization of the coating. The first step includes the 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, e.g. ethyl cellulose in cyclohexane12 (N-acetyl P-amino phenol as core),

· Addition of salt, e.g. addition of sodium sulphate solution to gelatine solution in vitamin encapsulation (Green 1960),

· Addition of non-solvent, e.g. addition of isopropyl ether to methyl ethyl ketone solution of cellulose acetate butyrate (Heistand et al. 1966) (methylscopalamine hydrobromide is core),

· Addition of incompatible polymer to the polymer solution, e.g. addition of polybutadiene to the solution of ethylcellulose in toluene (The National Cash Register Co. 1963) (methylene blue as core material) and

· Inducing polymer–polymer interaction, e.g. interaction of gum Arabic and gelatine at their iso-electric point (Brynko et al. 1967).

The second step includes deposition of liquid polymer upon the core material. Finally, the prepared microcapsules are stabilized by cross-linking, desolvation or thermal treatment Cross-linking is the formation of chemical links between molecular chains to form a three-dimensional network of connected molecules. The vulcanization of rubber using elemental sulphur is an example of crosslinking, converting raw rubber from a weak plastic to a highly resilient elastomer. The strategy of covalent crosslinking is used in several other technologies of commercial and scientific interest to control and enhance the properties of the resulting polymer system or interface, such as thermosets and coatings (DeBord and Schick 1999, Stevens 1999, Wicks et al. 1999). Cross-linking has been employed in the synthesis of ion-exchange resins (Dyson 1987) and stimuli-responsive hydrogels (Lowe and McCormick 1999) made from polymer molecules containing polar groups. As polyelectrolytes, hydrogels are inherently water-soluble. To make them insoluble, they are chemically crosslinked during manufacture or by a second reaction following that of polymerization of the starting monomers.

The degree of cross-linking, quantified in terms of the cross-link density, together with the details of the molecular structure, have a profound impact on the swelling characteristics of the cross-linked system. For example, derivatives of ethylene glycol di(meth)acrylate like, ethylene glycol diacrylate, di(ethylene glycol) diacrylate, tetra(ethylene glycol) diacrylate, ethylene glycol dimethacrylate, di(ethylene glycol) dimethacrylate, tri(ethylene glycol) dimethacrylate; derivatives of methylenebisacrylamide like N,N- Methylenebisacrylamide, N,NMethylenebisacrylamide, N,N-(1,2- Dihydroxyethylene) bisacrylamide (Kla¨rner et al. 1999), glutaraldehyde, sodium tripolyphosphate, etc. Yin and Sto¨ver (2003) prepared microspheres by poly (styrene-alt-maleic anhydride) partially grafted with methoxy poly (ethylene glycol) (SMA-g-MPEG) were prepared by reacting poly (styrene-alt-maleic anhydride) with a substoichiometric amount of MPEG lithium alcoholate. Aqueous solutions of the resulting SMA-g-MPEG formed complex coacervates with poly (diallyldimethylammonium chloride) (PDADMAC). These phase-separated liquid polyelectrolyte complexes were subsequently crosslinked by the addition of two different polyamines to prepare cross-linked hydrogel microspheres. Chitosan served as an effective cross-linker at pH 7.0, while polyethylenimine (PEI) was used as a cross-linker under basic conditions (pH 10.5).

The resulting coacervate microspheres swelled with increasing salinity, which was attributed mainly due to the shielding of the electrostatic association within the polyelectrolyte complex. Huang et al. (2007) prepared microcapsules by using gelatine and gum Arabic by coacervation. The most frequently used cross-linking agent formaldehyde in the gelatin– acacia microencapsulation process was altered by glycerol in this study. They found that the yield of gelatin– acacia microcapsules decreases at surfactant concentrations above or below the optimum. Inhibition of coacervation due to high concentrations of surfactants and disturbance of microencapsulation due to high hydrophilic– lipophilic balance (HLB) values have been reported. In general, the concentration of a surfactant required to increase the yield of microcapsules is too low to produce regular-sized droplets. The analysis of the size distribution shows that the microcapsules are multi-dispersed.

In the coacervation process, the pH value of a continuous gelatin phase would be adjusted above its isoelectric point to form negatively charged gelatin, which is able to create monodispersed droplets. The positively charged gelatin is attracted to the negatively charged acacia to form coacervate droplets when the pH value is adjusted to below its isoelectric point. [19,20]

Fig. 3: Coacervation process: (a) Core material dispersion in solution of shell polymer; (b) Separation of coacervate from solution; (c) Coating of core material by micro droplets of coacervate; (d) Coalescence of coacervate to form continuous shell around core particles.

Simple coacervation:

Simple coacervation involves the use of either a second more-water soluble polymer or an aqueous non-solvent for the gelatin. This produces the partial dehydration/desolvation of the gelatin molecules at a temperature above the gelling point. This results in the separation of a liquid gelatin-rich phase in association with an equilibrium liquid (gelatin-poor) which under optimum separation conditions can be almost completely devoid of gelatin.

Simple coacervation can be effected either by mixing two colloidal dispersions, one having a high affinity for water, or it can be induced by adding a strongly hydrophilic substance such as alcohol or sodium sulfate [17]. The watersoluble polymer is concentrated in water by the action of a water miscible, non-solvent for the emerging polymer (gelatin) phase. Ethanol, acetone, dioxane, isopropanol and propanol have been used to cause separation of coacervate of gelatin, polyvinyl alcohol and methyl cellulose. Phase separation can be effected by the addition of an electrolyte such as an inorganic salt to an aqueous solution of a polymer such as gelatin, polyvinyl alcohol or carboxymethyl cellulose.

A typical simple coacervation using gelatin colloid is as follows: to a 10 percent dispersion of gelatin in water, the core material is added with continuous stirring and at a temperature of 40°C. Then a 20 percent sodium sulfate solution or ethanol is added at 50 to 60 percent by final total volume, in order to induce the coacervation. This system is cooled to 50°C; then, it is necessary to insolubilize the coacervate capsules suspended in the equilibrium liquid by the addition of a hardening agent such as glutaraldehyde and adjusting the pH. The resulting microcapsules are washed, dried and collected [21].

Complex coacervation:

Complex coacervation' can be induced in systems having two dispersed hydrophilic colloids of opposite electric charges. Neutralization of the overall positive charges on one of the colloids by the negative charge on the other is used to bring about separation of the polymer-rich complex coacervate phase. The gelatin-gum arabic (gum acacia) system is the most studied complex coacervation system. Complex coacervation is possible only at pH values below the isoelectric point of gelatin. It is at these pH values that gelatin becomes positively charged, but gum arabic continues to be negatively charged. A typical complex coacervation process using gelatin and gum arabic colloids is as follows: The core material is emulsified or suspended either in the gelatin or gum arabic solution. The aqueous solution of both the gelatin and gum arabic should each be below 3 percent by weight. Then, the gelatin or the gum arabic solution (whichever was not previously used to suspend the core material) is added into the system. The temperature of the system must be higher than the gel point of an aqueous gelatin solution (greater than 35°C). The pH is adjusted to 3.8-4.3 and continuous mixing is maintained throughout the whole process. The system is cooled to 50°C and the gelled coacervate capsule walls are insolubilized by either adding glutaraldehyde or another hardening agent or adjusting the pH. The microcapsules are washed, dried and collected [22,23].

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 supersaturation 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.[24]

Particles from a gas-saturated solution (PGSS):

Rapid expansion of supercritical solution:

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. The disadvantage of this process is that both the active in- gradient and the shell material must be very soluble in supercritical fluids. In general, very few polymers with low cohesive energy densities (e.g., polydimethylsiloxanes, polymethacrylates) are soluble in supercritical fluids such as CO2. The solubility of polymers can be enhanced by using co-solvents. In some cases nonsolvents are used; this increases the solubility in supercritical fluids, but the shell materials do not dissolve at atmospheric pressure. A schematic of the microencapsulation process using supercritical CO2. It had very recently carried out microencapsulation of TiO2 nanoparticles with polymer by RESS using ethanol as a non solvent for the polymer shell such as polyethylene glycol (PEG), poly(styrene)-b-(polymethyl methacrylate)-copoly(glycidal methacrylate) copolymer (PS-b-(PMMA-co-PGMA) and polymethyl methacrylate) [26].

Fig. 4: Microencapsulation by rapid expansion of supercritical solutions

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 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. Within the pharmaceutical industry, preformed microparticles are often used for the entrapment of active materials using supercritical fluids under pressure. When the pressure is released, the microparticles shrink and return to their original shape and entrap the ingredients [27].

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 ring-shaped hardening bath. This process is excellent for forming particles 400–2,000 μm (16-79 mils) in diameter. Since the drops are formed by the breakup of a liquid jet, the process is only suitable for liquid or slurry. A high production rate can be achieved, i.e., up to 22.5 kg (50 lb) of microcapsules can be produced per nozzle per hour per head. Heads containing 16 nozzles are available [28].

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.

Fig. 5: Representation of typical Pan Coating

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 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 [29].

Fig. 6: List of variables affecting pan coating

Physico-mechanical process Spray drying and congealing. Microencapsulation by spray-drying is a low-cost commercial process which is mostly used for the encapsulation of fragrances, oils and flavours. Core particles are dispersed in a polymer solution and sprayed into a hot chamber (Figure 6). The shell material solidifies onto the core particles as the solvent evaporates such that the microcapsules obtained are of polynuclear or matrix type. Chitosan microspheres crosslinked with three different cross-linking agents viz, tripolyphosphate (TPP), formaldehyde (FA) and glutaraldehyde (GA) have been prepared by spray-drying technique.

The influence of these cross-linking agents on the properties of spray-dried chitosan microspheres was extensively investigated. The particle size and encapsulation efficiencies of thus prepared chitosan microspheres ranged mainly between 4.1–4.7 mm and 95.12–99.17%, respectively. Surface morphology, percentage erosion, percentage water uptake and drug release properties of the spray-dried chitosan microspheres was remarkably influenced by the type (chemical or ionic) and extent (1 or 2% w/w) of cross-linking agents. Spray-dried chitosan microspheres cross-linked with TPP exhibited higher swelling capacity, percentage water uptake, percentage erosion and drug release rate at both the cross-linking extents (1 and 2% w/w) when compared to those crosslinked with FA and GA. The sphericity and surface smoothness of the spray-dried chitosan microspheres was lost when the cross-linking extent was increased from 1 to 2% w/w. Release rate of the drug from spray dried chitosan microspheres decreased when the crosslinking extent was increased from 1 to 2% w/w. The physical state of the drug in chitosan-TPP, chitosan-FA and chitosan-GA matrices was confirmed by the X-ray diffraction (XRD) study and found that the drug remains in a crystalline state even after its encapsulation. Release of the drug from chitosan-TPP, chitosan-FA and chitosan- GA matrices followed Fick’s law of diffusion (Desai and Park 2005).

Spray congealing can be done by spray-drying equipment where protective coating will be applied as a melt. Core material is dispersed in a coating material melt rather than a coating solution. Coating solidification is accomplished by spraying the hot mixture into cool air stream. Waxes, fatty acids and alcohols, polymers which are solids at room temperature but meltable at reasonable temperature, are applicable to spray congealing. Albertini et al. (2008) prepared mucoadhesive microparticles and designed an innovative vaginal delivery system for econazole nitrate (ECN) to enhance the drug anti-fungal activity. Seven different formulations were prepared by spraycongealing, a lipid-hydrophilic matrix (Gelucire((R)) 53/ 10) was used as carrier and several mucoadhesive polymers such as chitosan, sodium carboxymethylcellulose and poloxamers (Lutrol((R)) F68 and F127) were added.[30]

Figure 7. Schematic illustrating the process of micro-encapsulation by spray-drying 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 (Figure 7).

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. Increased encapsulation efficiency and the prevention of cluster formation is achieved by opposing flows 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.[31]

Figure 8. Schematics of a fluid-bed coater. (a) Top spray; (b) bottom spray; (c) tangential spray.

In-situ polymerization:

In a few microencapsulation processes, the direct polymerization of a single monomer is carried out on the particle surface. In one process, E.g. Cellulose fibers are encapsulated in polyethylene while immersed in dry toluene. Usual deposition rates are about 0.5μm/min. Coating thickness ranges 0.2-75μm. The coating is uniform, even over sharp projections [32].

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 perm selectivity, 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 [33].

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 [34-36].

Fig. 9: 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.

· Hygroscopic properties of core materials may be 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. vitamin 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.

Factors influencing encapsulation efficiency The encapsulation efficiency of the microparticle or microcapsule or microsphere will be affected by different parameters. Figure 5 illustrates the factors influencing encapsulation efficiency.[37]

Figure 10. Factors influencing encapsulation efficiency.

Characterization of microcapsule:

The characterization of the micro particulate 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 [38].

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 (10mm in diameter, 10 mm in height) by using a double-sided adhesive tape. The specimens are coated at a current of 10mA for 4 min using an ion sputtering device (JFC-1100E, Jeol, Japan) [39].

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 [40].

Particle size:

Particle size determination approximately 30mg microparticles is redispersed in 2–3ml 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 60ml/s. The microparticle size can be determined by laser diffractometry using a Malvern Mastersizer X (Malvern Instruments, UK) [41]

Polymer solubility in the solvents:

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 solvent.

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 400C is 0.0038 mm2/s/s) at 25 ± 0.10C in a thermostatic bath. The polymer solutions are allowed to stand for 24 h prior to measurement to ensure complete polymer dissolution [42].

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 [43].

Bulk density:

The microspheres fabricated are weighed and transferred to a 10-ml glass graduated cylinder. The cylinder is tapped using an auto trap (Quantach- Rome, FL, USA) until the microsphere bed volume is stabilized. The bulk density is estimated by the ratio of microsphere weight to the final volume of the tapped microsphere bed.

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.

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 200° within a minute of deposition of microspheres [44].

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 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 [45].

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 50-500ml and the stirrer speed form 60-300rpm [46].

Dissolution apparatus:

Standard USP or BP dissolution apparatus have been used to study in vitro release profiles using both rotating elements (paddle and basket). Dissolution medium used for the study varied from 100-500ml and speed of rotation from 50-100rpm.

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 [47].

CONCLUSION:

Microencapsulation means packaging an active ingredient inside a capsule ranging in size from one micron to several millimeters. The capsule protects the active ingredient from its surrounding environment until an appropriate time. Then, the material escapes through the capsule wall by various means, including rupture, dissolution, melting or diffusion. Microencapsulation is both an art and a science. There's no ONE way to do it, and each new application provides a fresh challenge. Solving these riddles requires experience, skill and the mastery of many different technologies.

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Received on 22.01.2020 Modified on 15.02.2020

Asian J. Res. Pharm. Sci. 2020; 10(1):39-50.

DOI: 10.5958/2231-5659.2020.00009.0