Ill A single wallforming polymer soluble in an organic liquid

Addition of a miscible liquid, a non-solvent for the polymer

In this process, the polymer is dissolved in an appropriate organic solvent, then a non-solvent, which is miscible with the polymer solvent, is used to induce phase separation. The non-solvent may be organic or an aqueous liquid (Kondo, 1979a). Frequently, low polymer concentrations are used, along with gradual phase separation to promote appropriate encapsulation. This permits the polymer solution to deposit onto the core and at the same time, flow evenly. The formation of high polymer concentrations tends to provide a demixing effect. The demixing effect and coacervation are best explained by phase diagrams. In Fig. 1 the line AKB represents the formation of a new phase. If the original concentration of polymer is on the SD, and heptane is added, a coacervate is formed; however, if the original concentration is on the line DP and heptane is added, then the polymer tends to come out of solution in a form that is not satisfactory for coating (Kondo, 1979a).

An example of this process is the encapsulation of magnesium hydroxide with ethylcellulose, using dichloromethane as the solvent and effecting phase separation with n-hexane as the non-solvent (Kasai and Koishi, 1977). Aqueous solutions of dyes have been encapsulated by this process. The

(tetrachloroethane-phenol)

(tetrachloroethane-phenol)

Fig. 1 Ternary diagram showing the phase-separation region of a mixture of polyethylene terephthalate, phenol, and heptane: AB, binodal curve; K, critical point. Reproduced with permission from Kondo (1979a), Microcapsule Processing and Technology, p. 96. Marcel Dekker,

Fig. 1 Ternary diagram showing the phase-separation region of a mixture of polyethylene terephthalate, phenol, and heptane: AB, binodal curve; K, critical point. Reproduced with permission from Kondo (1979a), Microcapsule Processing and Technology, p. 96. Marcel Dekker,

aqueous solution was dispersed in a solution of ethylcellulose dissolved in toluene containing a surface-active agent to assist emulsification. The miscible non-solvent, petroleum ether, was added to induce phase separation of the polymer onto the aqueous droplet (Reyes, 1965). Kondo (1979a) provides an extensive list of polymers, solvents and non-solvents. Some of the polymers are ethylcellulose, cellulose acetate butyrate, polyethylene and polyisobutyl methacrylate. The removal of the residual solvent from the product may be accomplished by washing with more non-solvent or by drying.

Change of temperature

This method of inducing phase separation depends upon the difference in solubility of the coating polymer as the temperature changes. For example, ethylcellulose is dissolved in the solvent, cyclohexane, at about 80°C and as the solution is allowed to cool the coacervate which is formed surrounds the core material which is dispersed throughout the system by appropriate stirring. This process was described by Fanger etal. (1970) who reported that after cooling to harden the product, an aggregated product was formed. This system has been studied in detail by Jalsenjak etal. (1976). It was found that the procedure was sensitive to minor changes in the procedure. Stirring speed, the vessel geometry and the rate of cooling affected the size distribution of the product, the amount of aggregation, surface characteristics and porosity.

Addition of an incompatible polymer or non-wall-forming polymer

This method of preparing microcapsules by coacervation is similar to the one previously described, in that while temperature is a main factor used to effect phase separation, an incompatible polymer is added to the system in order to aid in the induction of coacervation and/or to minimize the aggregation of microcapsules so that a more uniform product is obtained. As an example of this method, a suspension of the core, aspirin, in a solution of ethylcellulose and polyethylene of low molecular weight in cyclohex-ane was prepared at 80° C. Upon cooling slowly to room temperature the ethylcellulose separates from solution to surround the core. The polyethylene precipitates from solution in the form of fine particles. The purpose of the polyethylene is not clear, but may aid in the coacervation of the ethylcellulose and also minimize the coalescence of microcapsules prior to hardening of the walls (Kondo, 1979a).

Other incompatible polymers are butyl rubber, polybutadiene, and polydimethylsiloxane. Polyisobutylene, another polymer, apparently acts as a protective colloid and minimizes the formation of agglomerates of ethylcellulose (Deasy, 1984b). Polyisobutylene also promotes the formation of smooth, non-aggregated droplets and it has been shown that it is not incorporated into the wall (Benita and Donbrow, 1980).

After the capsules have been hardened, it is necessary to remove the incompatible polymer. This is readily accomplished, if the polymer remains in solution as the temperature is lowered, by filtration and rinsing the product, or by sieving if the incompatible polymer has a different particle size than the microcapsules.

Evaporation, with a miscible liquid, a non-solvent for the polymer

In this process the polymer is dissolved in an appropriate solvent and then another liquid, the suspending vehicle which has a higher boiling point and which is miscible with the polymer solvent is added. However, this liquid is a non-solvent for the polymer. Prior to evaporation the system is one phase, not including the core which may be added to the polymer solution either before or after mixing with the miscible liquid. During evaporation the polymer separates from solution forming liquid droplets, which are dispersed in the suspending liquid and these coat the core material (Fong, 1988).

An example of this process is the microencapsulation of drug ionexchange resin complex. The core was dispersed in a solution of polyiso-butylene dissolved in cyclohexane, and light liquid paraffin was added. A solution of ethylcellulose in ethylacetate was then added and evaporation allowed to proceed. The microcapsules were treated with cyclohexane, filtered and washed to remove the suspending liquid (Moldenhauer and Nairn, 1990).

Evaporation with an immiscible polar liquid, a non-solvent for the polymer

The core is dissolved or dispersed in an organic liquid, which contains the dissolved polymer and which has a relatively high vapour pressure and is immiscible with water. This mixture is dispersed in water, the immiscible liquid a non-solvent for the polymer, usually contains surface-active agents or a soluble viscosity agent which aid the formation and stabilization of the resulting oil/water (o/w) emulsion. The organic solvent is removed using heat or by reducing pressure. As the organic solvent is removed, the polymer solution becomes concentrated and phase separation of the polymer occurs with the result that the dispersed or dissolved core is entrapped in the polymer matrix (Hui etal., 1987).

As an example of the above, sulfathiazole was dispersed in a solution of ethylcellulose in chloroform. This mixture was then dispersed in an aqueous solution of sodium Iauryl sulfate to form an emulsion. After stirring for several hours, the organic solvent evaporated, resulting in the formation of ethylcellulose microcapsules. Other polymers used in this process include polylactic acid, polystyrene, and a large number of hydrophobic polymers (Kondo, 1979a; Deasy, 1984a).

The yield of microencapsulated products is high if the core material has a low solubility in water, otherwise the core will partition into the aqueous phase. The partitioning effect can be decreased if the aqueous phase contains salt, which decreases the solubility of the core in the aqueous phase, or by adjusting the pH to decrease the water solubility of the drug. Improved yields of drug can be achieved if the organic solvent has some solubility in water. These solvents then cause rapid deposition of the polymer at the interface, thus forming a barrier that decreases the rate of partitioning of the core into the aqueous phase (Watts etal., 1990).

If the core is an aqueous solution or suspension, it is first dispersed in the polymer solution to give a water/oil (w/o) emulsion and when this is added to the aqueous solution containing the surface-active agent and/or viscosity agent, a water/oil/water (w/o/w) emulsion is formed. The capsule size is influenced by factors such as the viscosity of the starting liquid, agitation speed, and the temperature. It has been suggested that if suitable surfactants are used to prepare the dispersion of the aqueous phase in the polymer solution, small capsules may be prepared with a size of =10^m (Kondo, 1979a).

An example of this process is the encapsulation of an aqueous solution of an enzyme. This solution is added to a 5 or 10% solution of a polystyrene dissolved in benzene and a primary emulsion is formed by means of a homogenizer. This primary w/o emulsion is then dispersed in an aqueous solution containing a viscosity agent such as gelatin to form the w/o/w emulsion. The temperature is raised to 40°C with constant stirring until the benzene dissolves in the aqueous layer and is removed by evaporation. The polymer is deposited around the aqueous enzyme solution to form the shell wall (Kondo, 1979a).

One difficulty with the process is the time it takes to remove the solvent from the polymer solution, as it is immiscible with the water phase even if the preparation is subjected to heating and reduced pressure. Other techniques used to remove the polymer solvent include freeze drying or adding a solvent that is miscible with water and the polymer solvent but a non-solvent for the polymer (Kondo, 1979a).

A modification of the above process has been called the interfacial deposition technique. In this particular process, «-heptane was emulsified in an aqueous solution of Pluronic F68, an emulsifier, to give an o/w emulsion. A solution of dichloromethane containing either poly (L-lactide) or poly (DL-lactide) was added dropwise to the emulsion which was stirred under partial vacuum. The polymer deposited at the surface of the n-heptane droplets to yield small microcapsules containing water (Makino etal., 1985).

Evaporation or removal with an immiscible organic liquid, a non-solvent for the polymer

This process is especially useful for the preparation of microencapsulated, water-soluble compounds. The drug is dissolved or dispersed in the solution of the organic polymer and this is then dispersed into another organic liquid, usually mineral oil; as a result, an oil/oil (o/o) emulsion or separate phase is formed. The inner phase contains the drug and the polymer and the outer phase is mineral oil. The solvent for the polymer may be partially extracted by the mineral oil and/or may be allowed to evaporate. The resulting microcapsules are filtered and washed with a non-solvent which removes the solvent for the polymer and the mineral oil.

A number of drugs and vaccines have been prepared in microcapsule form in cellulose acetate phthalate in this manner. For example, the drug or vaccine is dispersed in mineral oil, with or without sorbitan monooleate, with stirring and then an acetone-ethanol solution of cellulose acetate phthalate is added. The polymer separates and entraps the drug; after some evaporation has taken place, the mixture is treated with chloroform, filtered and further treated with chloroform (Maharaj etal., 1984; Beyger and Nairn, 1986).

Some investigators, after decanting the excess mineral oil from an ethyl-cellulose ethylacetate system, have placed the product directly in soft gelatin capsules (D'Onofrio etal., 1979).

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