It was found that the time for release of sodium phenobarbitone from ethylcellulose microcapsules increased as the core:wall ratio decreased. With a constant core: wall ratio, the small microcapsules released their contents more rapidly than the larger ones (Jalsenjak etal., 1976).

In a series of papers Donbrow and Benita (1977) investigated the effect of polyisobutylene on the coacervation of ethylcellulose. Ethylcellulose and polyisobutylene were dissolved in cyclohexane and the solution was allowed to cool slowly from 80°C to 25°C with controlled agitation. After 24 h, a clear upper phase containing the polyisobutylene and a lower phase of coacervate droplets formed whose particle size decreased with phase coacervation volume increase, which was increased by polyisobutylene. The product was a free-flowing powder, in contrast to the aggregated mass in the absence of polyisobutylene. The release of salicylamide from microcapsules showed first-order kinetics and the release rate increased with polyisobutylene concentration because of the thinner coating. It was indicated that polyisobutylene acts as a protective colloid in the process and prevents the agglomeration of ethylcellulose microcapsules.

Benita and Donbrow (1980), in a second paper, indicated that using a temperature reduction method for preparing coacervation droplets, in the absence of, or a low concentration of polyisobutylene, aggregates were formed, whereas higher concentrations of polyisobutylene stabilized the droplet. Polyisobutylene is not coprecipitated and acts as a stabilizer by adsorption. Increased concentration of polyisobutylene or higher molecular weights of polyisobutylene raised the phase coacervation volume and decreased the particle size indicating increased stabilization.

Benita and Donbrow (1982) employed polyisobutylene as a protective colloid to prepare microcapsules of salicylamide and theophylline based on the temperature differential solubility of ethylcellulose in cyclohexane. A minimum concentration of polyisobutylene was necessary to prevent aggregation and as its concentration was increased, it yielded microcapsules of higher drug content because the coating was thinner; furthermore, there was an increase in the release rate of the drug from the microcapsules. Microcapsule drug content decreased with decreasing particle size of the drug in the presence of the protective colloid. This was caused by a more complete uptake of the wall polymer on the increased surface of the core material.

A mixture of ethylcelluloses with a viscosity of lOOcp (0.1 Pas) and a viscosity of 45 cp (0.045 Pa s) was used to encapsulate trimethoquinol using polyisobutylene as an agent to induce phase separation. The mixture was cooled from 78°C to room temperature and the microcapsules were filtered, washed and dried (Samejima and Hirata, 1979).

Samejima etal. (1982) prepared microcapsules of ascorbic acid with ethylcellulose using the temperature change technique. They found that polyisobutylene was better than either butyl rubber or polyethylene. The polyisobutylene changed the gel into a coacervate with the formation of smooth microcapsules with thick walls. The microcapsules did not aggregate appreciably and gave a slow release of the vitamin.

In a subsequent paper, Koida etal. (1983) used a similar method to encapsulate ascorbic acid with ethylcellulose using polyisobutylene. It was found that aggregation decreased with increasing molecular weight of ethylcellulose. The molecular weight of ethylcellulose which gave a minimum release rate was affected by the molecular weight of polyisobutylene. Polyisobutylene of high molecular weight gave less aggregation than polyisobutylene of low molecular weight. The relationship between the release rate and the molecular weight of ethylcellulose used depended primarily on the compactness of the wall, rather than its thickness.

In a patent, Samejima etal. (1984) described the encapsulation of trime-butine maleate with ethylcellulose using liquid paraffin and polyisobutylene in cyclohexane to give a solubility parameter of 7-10 (cal cm"3)172, and then subsequent cooling. The product was free-flowing microcapsules.

Koida etal. (1984) investigated the effect of molecular weight of polyisobutylene on the microencapsulation of ascorbic acid using temperature reduction with a solution of ethylcellulose. After fractionating polyisobutylene, several fractions of various molecular weights were obtained. It was found that aggregation of the microcapsules decreased with increasing M (viscosity-average molecular weight), and above a value of 6 x 105 it was almost wholly prevented. The influence of Mof polyisobutylene on the coacervation process was determined by measuring the volume fraction, the ethylcellulose content and the viscosity. It was found that the wall-forming temperature was lower with higher M of polyisobutylene. With higher M of polyisobutylene, a larger coacervation volume was produced, but the concentration of ethylcellulose in the coacervation phase was less and there was a very low concentration of polyisobutylene in the coacervate phase. The viscosity of the coacervate phase was higher with the lower Mof polyisobutylene; this was attributed to the higher concentration of ethylcellulose in the coacervate. It was found that the temperature of the viscosity maximum coincided with the wall-forming temperature which appeared to be the most important temperature for microencapsulation. As the temperature decreases and reaches the temperature of maximum viscosity, the size of the ethylcellulose droplets gets larger and these gel-like droplets deposit on the surface of the drug and, after fusing, they form the wall. The effect of mixing high and low A/polyisobutylene showed that with an increase of low M polyisobutylene, average wall thickness and compactness increases and the wall becomes less uniform.

Several different techniques have been employed to encapsulate ionexchange resin beads containing benzoate with ethylcellulose by temperature change and non-solvent addition (Motycka and Nairn, 1979). Different viscosity grades of ethylcellulose, either alone or in conjunction with various plasticizing agents such as castor oil, butyl stearate and the protective colloid polyethylene were used. Some of these products were then treated with paraffin. In addition, the benzoate complex was encapsulated using gelatin and acacia and also cellulose acetate butyrate. It was found that the rate of release, as described by Boyd etal. (1947), could be controlled by the type of encapsulating material used and the phase separation process. The slowest rate of release was achieved with the microcapsules which were subsequently treated with paraffin. It was found that tough, dense films of large molecular weight compounds delayed the release of the anion. The decrease in the diffusion of the benzoate ions corresponded with an increase of the density of the film. Additives with the greatest lipophilic characteristics, polyethylene and paraffin produced the greatest resistance to ion transfer.

In a subsequent paper, Motycka etal. (1985) encapsulated ion-exchange resin beads containing theophylline with ethylcellulose, inducing phase separation by temperature reduction and by evaporation. Some of the products were subsequently treated with a solution of hard paraffin. Several products encapsulated with ethylcellulose by evaporation and also subsequently treated with a solution of hard paraffin gave a product that released the drug according to zero-order kinetics. It was found that the pattern and the rates of release could be controlled by the cross-linking of the resin and the coating procedure used.

Ethylcellulose microcapsules of ion-exchange resins containing theophylline were prepared by the evaporation method using ethylcellulose dissolved in ethyl acetate as the coating polymer, polyisobutylene dissolved in cyclo-hexane as a protective colloid and light liquid paraffin as the suspending medium (Moldenhauer and Nairn, 1990). Predominantly mononucleated microcapsules were formed by controlling the amount of ethylcellulose used, the particle size and the appropiate concentration of the protective colloid. The rate of release of the drug was altered by the cross-linking of the ion-exchange resin, the amount of ethylcellulose and the smoothness of the coat on the resin beads. Release rates from coated resin beads with low cross-linking followed a logarithmic plot indicating membrane controlled release, whereas coated resins with a higher degree of cross-linking followed a txn plot, indicating particle diffusion control.

In a subsequent paper, Moldenhauer and Nairn (1991) investigated the effect of the rate of evaporation on the coat structure of the microcapsules which were predominantly mononucleated. The rate of solvent evaporation influenced the surface morphology, the shape, and the porosity and the purity of the ethylcellulose coat. Microcapsules had tails and porous coats at slow evaporation rates. Faster evaporation rates resulted in the formation of microcapsules with no tails and smooth, but wrinkled coats. Coat porosity was minimal at intermediate evaporation rates. Microcapsules which showed rapid release rates of theophylline were formed when the very fast, slow and very slow evaporation rates were used to form the microcapsules. Intermediate evaporation rates formed coats with minimum porosity, leading to slow release rates of the drug.

Baichwal and Abraham (1980) encapsulated metronidazole by using ethylcellulose and polyethylene glycol 4000 in different proportions. As a result of encapsulation, the release of the drug was delayed and the percentage drug release, as a function of time, increased with increasing content of the polyethylene glycol.

Ascorbic acid has also been encapsulated using a solution of ethylcellulose in cyclohexane. The product had 2-3% wall material and a wall thickness of 6-10 /an (Shopova and Tomova, 1982).

Adriamycin was encapsulated with ethylcellulose in cyclohexane using the temperature reduction method (Kawashima etal., 1984). Polyisobutylene, rather than polyethylene, was found to be an effective coacervate-inducing agent. With increasing concentration of polyisobutylene, the average diameter of the particles decreased owing to reduced agglomeration. Microcap-

sules of the drug encapsulated with ethylcellulose at 2% polyisobutylene effectively prolonged the release of the drug compared with 1% or 3% polyisobutylene. The increase in rate of release noted when 3% polyisobutylene was used was attributed to a thinner wall. Kinetics of release of microcapsules prepared with 2% polyisobutylene were linear when plotted against tin suggesting a matrix type of release.

Using a non-solvent which resulted in the formation of an emulsion, Kaeser-Liard etal. (1984) encapsulated phenylpropanolamine hydrochloride with ethylcellulose. The drug, 95% of the particles <40 /¿m, was suspended in a solution of ethylcellulose dissolved in acetone. With stirring, a solution of equal volumes of mineral oil and petroleum ether, the nonsolvent, were added over 90min. During this period, the first emulsion of non-solvent in the polymer solution inverted to an emulsion of the polymer solution in the non-solvent at the same time phase separation took place. The microcapsules were then hardened with the addition of hexane at —20°C. After stirring in the cold, the microcapsules were filtered and dried. The microcapsules had a particle size in the 150-300 /¿m range and the yield was 90-100%. Several parameters were investigated, namely the volume of the non-solvent, the volume of the solidifying agent, rate of addition of the non-solvent, stirring rate, temperatures of the coacervation step and the hardening step and the core to wall ratio. The rate of drug release increased as the volume of the non-solvent was increased from 300 to 400 ml, as the temperature of hardening was increased from — 10°C to room temperature, and as the core to wall ratio was changed. The rate of addition of the nonsolvent and the stirring speed did not affect the drug release from the microcapsules.

Sulfamethoxazole was encapsulated with ethylcellulose using an emulsion technique by Chowdary and Rao (1984). The drug was dispersed in a solution of ethylcellulose in acetone. This dispersion was added in a thin stream to stirred liquid paraffin which formed an emulsion. Water, the nonsolvent, was then added to cause coacervation and production of the microcapsules. After centrifugation, the product was washed with petroleum ether and then dried. Batches of microcapsules were prepared using different core to coat ratios. The time for 50% of the drug to be released in an acidic and neutral medium increased as the particle size increased and as the percentage of the coat material increased.

Chowdary and Rao (1985) described the influence of Span 60 and Span 80 on the preparation of microcapsules by emulsification. It was found that the inclusion of surfactants decreased the microcapsule size, but did not alter drug release. The drug release with or without a surfactant was similar for a particular size of microcapsule.

Chowdary and Annapurna (1989) encapsulated aspirin, metronidazole, paracetamol and tolbutamide by three different methods. Method I was coacervation-phase separation of ethylcellulose dissolved in toluene by the addition of petroleum ether. Method II was similar except that carbon tetrachloride was used as the solvent. Method III used thermal induction of the coacervate of ethylcellulose from cyclohexane. In all cases the drug was added to the polymer solution. The wall thickness was determined by the method of Luu etal. (1973). The apparent dissolution rate constants, Ajpp, were calculated from the initial slope of the release curve as described by Koida etal. (1986). The permeability constants, Pm, were determined from the following equation:

Pm = KmVH ACs where V is the volume of the dissolution medium, H is the wall thickness of the microcapsules, A is the surface area of the microcapsules, and Cs is the solubility of the core in the dissolution medium.

The wall thickness ranged from 7.9 to 39.3 /tm and the apparent dissolution rate constant ranged from 0.53 to 12.32 mgmin-1. It was found that for all four cores the order of permeability of the microcapsules was method III > method I > method II which suggests that the permeability depends upon the method employed.

Rak etal. (1984) prepared potassium chloride microcapsules using ethylcellulose by phase separation from cyclohexane by temperature change. It was noted that the addition of macrogol 300 or 4000 improved the formation of microcapsules and decreased the aggregation of the product.

Potassium chloride was encapsulated with ethylcellulose by coacervation with cyclohexane using polyethylene glycol by Chalabala (1984). The drug, with a particle size of 80 /im, had a microcapsule size of 125-187 ^m with agglomerates up to 605 ^m. High core to wall ratios gave smaller microcapsules.

Szretter and Zakrzewski (1984a) coated riboflavin with ethylcellulose dissolved in cyclohexane by the temperature change method. The solution also contained PEG 6000 and Tween 20. The product was stable at room temperature against oxidation, photodecomposition and humidity. The vitamin was also encapsulated with PEG 6000 by mixing at 70° C with paraffin oil, and ligroin containing PEG 6000 and Span 60 or Tegin G. The suspension was cooled to room temperature, filtered, washed and dried.

A mixture of ethylcellulose and polyethylene glycol 6000 has been used as a coating material and the process is carried out in cyclohexane to improve the stability of ascorbic acid (Szretter and Zakrzewski, 1987a).

Cisplatin was encapsulated with ethylcellulose dissolved in cyclohexane in the presence of low density polyethylene by the temperature reduction method (Hecquet etal., 1984). Two stirring methods were used during the cooling stage - mechanical and sonication; however, no difference in microcapsule characteristics could be discerned between the methods. A number of different concentrations of drug, ethylcellulose and polyethylene were used to prepare the microcapsules and several observations were made: (a) losses of microencapsulated drug content occurred on increasing the ethylcellulose concentration; (b) the average drug content did not change if the amount of polyethylene was increased, but the proportion of small-size microcapsules increased; (c) the microcapsule composition appeared to be independent of particle size; (d) the wall thickness increased with an increase of ethylcellulose concentration. The drug was not decomposed by the microencapsulation process and certain products which released 80100% of the drug within 24 h were selected for further studies.

Encapsulation of rifampicin was effected by dissolving ethylcellulose in ethyl acetate and adding the drug mixture. After stirring for 4 h petroleum ether was added at a controlled rate until coacervation started and then the mixture was stirred for 1 h. The microcapsules were collected, washed, dried and eventually made into pellet form (Khanna etal., 1984).

Dihydralazine sulfate was encapsulated with ethylcellulose by Oner et al. (1984). The microcapsules were separated by size. The time for half of the drug to be released increased as the core to wall ratio decreased and as the particle size increased. Release appears to take place by diffusion.

Oner etal. (1988) encapsulated zinc sulfate using ethylcellulose dissolved in carbontetrachloride. Warm petroleum ether, a non-solvent, was added and the product was collected and washed with the non-solvent and dried. The rate of release in distilled water was determined and evaluated kinetically by the Rosin-Rammler-Sperling-Bennet-Weibull Distribution, which gave a good fit in defining the release from the microcapsules. A comparison of the release with hard gelatin capsules was also made.

Lin etal. (1985) encapsulated theophylline with ethylcellulose using four types of ethylene vinyl-acetate copolymer, with different concentrations of vinyl acetate (20-40%) as a coacervation-inducing agent. When /i-hexane was added at the last step of microencapsulation, the particles aggregated except for the polymer containing 28% vinyl acetate. Using increasing concentrations of this polymer decreases the average diameter of the microcapsules as there was less aggregation. The wall thickness, the smoothness and compactness of the microcapsules increased and the porosity decreased with increasing concentration of the coacervating-inducing polymer. Differential scanning calorimetry indicated that the coacervate-inducing polymer was absent in all microcapsules.

Lin (1985) then investigated the influence of the coacervation-inducing agent ethylene vinyl acetate and polyisobutylene and cooling rates on the properties of microencapsulated bleomycin HC1. The particle size of microcapsules induced by ethylene vinyl acetate was smaller than that induced by polyisobutylene, and the size distribution of microcapsules using ethylene vinyl acetate depended on the cooling rate, which was different from that using polyisobutylene. The slower the cooling rate, the more prolonged was the release of the drug; this followed the Higuchi model. The time required for dissolution of 50% of the drug for both methods of microcapsule preparation decreased with an increase in the cooling rate. The rate-limiting step under certain circumstances was diffusion of the dissolution medium and the dissolved drug through ethylcellulose.

In a subsequent study, Lin and Yang (1986a) encapsulated chlorproma-zine HC1 with ethylcellulose using ethylene vinyl acetate copolymer as a coacervation-inducing agent. Higher concentrations of ethylene vinyl acetate decreased the microcapsule size and delayed the release of the drug because of the more compact surface and increased thickness of the wall. Microcapsules were compressed into tablets and prolonged the release considerably, which was attributed to a reduced surface area.

The release mechanism was discussed by Lin and Yang (1986b), and it was found that differential rate treatments showed that the release kinetics of theophylline from ethylene vinyl acetate copolymer-induced ethylcellulose microcapsules followed first-order kinetics.

Lin and Yang (1987) also encapsulated theophylline with ethylcellulose by temperature change using ethylene vinyl acetate copolymer as a coacervation-inducing agent. It was found that the higher the concentration of copolymer used, the more sustained was the release of the drug from the microcapsules. This was attributed to the lower porosity and thicker walls of the microcapsule. Bioavailability studies in rats indicated that microcapsules prepared with higher concentrations of ethylene vinyl acetate may act as sustained release forms.

Lin (1987) also investigated the effect of polyisobutylene of different molecular weights on the release behaviour of theophylline from microcapsules prepared with ethylcellulose. It was found that the release rate of the drug at pH values of 1.2 and 7.5 at 35°C was higher when polyisobutylenes with higher molecular weights were used. This was similar to results reported by Koida etal. (1984). Several equations were investigated to study the release behaviour and one of the most useful was l/y = A 1/x + B where y is the amount of drug released, x is the time, and A and B are constants that are proportional to the amount of drug released.

Cameroni etal. (1985) encapsulated sulfadiazine by phase separation coacervation using temperature change and ethylcellulose and polyisobutylene was used as a protective colloid. Different release rates could be obtained by altering the wall thickness, which was controlled by the formulation. The rate of release for wall thickness <5 /¿m followed the Hixson-Crowel theory and that for greater wall thickness followed the Higuchi theory.

Encapsulation of indomethacin and indomethacin modified by dry blending with a carboxyvinyl polymer by pulverization was carried out by Naka-jima etal. (1987), with ethylcellulose and temperature reduction using polyethylene as a coacervation-inducing agent. The microcapsules were multinucleated and released the drug very slowly in a dissolution medium of pH 7.2. The rate of dissolution decreased as the amount of polyethylene was increased in the coacervation process. Subsequently, the microcapsules were prepared in the form of suppositories and were tested for dissolution characteristics.

Singh and Robinson (1988) investigated the effects of a number of surfactants on microencapsulation. Tweens and Spans, with HLB values ranging from 4.7 to 15, were used for the preparation of microcapsules of captopril. The process was carried out by dissolving the ethylcellulose in cyclohexane containing 2% absolute alcohol at 80°C. After dispersing the drug in this solution, it was cooled to room temperature and then to about 0°C. Microcapsules retained by 500-850 ptm sieves were used for further studies. Dissolution tests in 0.1 N HC1 at 37 °C showed that the release rate decreased with an increase in the HLB of the surfactant. Based on the work of Barnett and Zisman (1959), who indicated that many solids will not be wetted if their critical surface tension is exceeded by the surface tension of the liquid, the authors suggested that the wetting for solvation of ethylcellulose with surfactants of higher HLB values resulted in an efficient coating around the drug particles and thus caused the slowest release. It was also found that higher ethylcellulose viscosity grades were less effective in extending the release of the drug in the concentrations used. This was attributed to the high viscosity of the coacérvate droplets which inhibited coalescence and thus the formation of an intact ethylcellulose wall. Different kinetic models were used to explain the release. The best fit was the first-order kinetics plot with two straight lines that had two different slopes. The initial slope has a faster release than the terminal slope.

In a second paper, Singh and Robinson (1990) investigated the encapsulation of captopril using four viscosity grades of ethylcellulose with core to wall ratios of 1:1, 1:2, 1:3 by temperature reduction in cyclohexane. Dissolution studies in acidic media showed that the release depended upon the core to wall ratio and the viscosity grade of ethylcellulose and probably on the viscosity of the coacervate. A core to coat ratio of 1:1 showed that an increase of viscosity of wall material decreases the release rates. Viscosity grade 300 cp was not satisfactory for microencapsulation. The surface, as studied by scanning electron microscopy, showed that microcapsules prepared with 10 cp ethylcellulose were more porous and with larger pores than those prepared with 50 cp. The microcapsules did not fragment, alter shape or size or show enlargement of pores during dissolution. The in vitro release correlated better with biphasic first-order kinetics, rather than zero order or square root of time.

Singla and Nagrath (1988) encapsulated ascorbic acid to improve its stability in the presence of zinc sulfate. The microcapsules were prepared using ethylcellulose and the temperature change method using toluene as a solvent. The microencapsulated ascorbic acid was washed with toluene and dried in a vacuum. Several formulations including the product just described, ascorbic acid embedded in PEG 6000 or in stearic acid, were prepared in the form of tablets along with zinc sulfate. Tablets prepared from either the microcapsules or the stearic acid product had the maximum stability.

Based on a factorial design, the parameters which influence the particle size and particle size distribution of acetylsalicylic acid microcapsules coated with ethylcellulose were determined (Devay and Racz, 1988). The microcapsules were prepared by dissolving the drug and the polymer in varying ratios in diethylether in a reflux apparatus with stirring at 30°C. The solution was placed under vacuum and upon boiling, n-hexane was added slowly and the temperature reduced to 20°C; after filtration the microcapsules were dried. It was noted that the drug precipitated first and then became coated with the polymer. Coacervation was attributed to evaporation of the solvent, addition of a non-solvent and cooling. The parameters affecting the particle size for 50% through fall are in the order, rate of addition of hexane > drug content > ethylcellulose viscosity > speed of agitation. It was found that the standard deviation of the size increased with drug content, polymer viscosity, rate of addition of hexane and decreased with speed of addition.

Ferrous fumarate was encapsulated by phase separation using different ratios of ethylcellulose and castor oil. It was found that the drug release from the microcapsules depended upon the particle size, the thickness of the coat and the core:coat ratio (Shekerdzhiiski etal., 1988).

Metoprolol tartrate was encapsulated with ethylcellulose using two different coacervation techniques by Nasa and Yadav (1989). In the non-solvent method, ethylcellulose was dissolved in a solution of carbon tetrachloride and the drug was added, then petroleum ether and talc. After decanting, the microcapsules were filtered and washed with petroleum ether. The second method involved temperature change of a solution of the polymer in cyclohexane. The product was filtered and washed with hexane and dried. It was found that the dissolution rate in distilled water of the product prepared by the use of the non-solvent gave a slower dissolution. Furthermore, as the concentration of ethylcellulose used in preparing the microcapsules increased, the dissolution rate decreased. Stability studies of both pure drug and microencapsulated drug showed similar results.

The effect of hydroxypropyl methylcellulose as a nucleating agent was investigated using ethylcellulose and temperature change to effect microencapsulation. The core contained ascorbic acid, PEG 4000 and the nucleating agent. Optimum conditions for the formation of microcapsules, such as cooling, temperature, time, and concentration of hydroxypropyl methylcellulose, were assessed (Kaltsatos etal., 1989).

Safwat and El Shanawany (1989) treated theophylline and oxyphen-butazone with a carboxyvinyl polymer, Carbopol CV 940, by dry blending to control their release. The coated drugs were encapsulated with ethylcellulose using polyethylene and temperature reduction. The release rates of the two drugs decreased as the content of polyethylene, a coacervation-inducing agent, was increased, except at a concentration of 1% with the drug oxyphenbutazone. Suppositories containing the microencapsulated carboxyvinyl polymer modified drugs showed a pseudo zero-order release profile. It was felt that this method, that is, surface treatment and microencapsulation, is a good one to prepare sustained release suppositories containing these drugs.

Vitamin C was encapsulated with ethylcellulose in cyclohexane using ethylene polymer as the coacervation-inducing agent. It was found that the dissolution rate of the microencapsulated vitamin and tablets was slower than unencapsulated samples (He and Hou, 1989).

Shin and Koh (1989) investigated the effect of polyisobutylene on the preparation of methyldopa encapsulated with ethylcellulose dissolved in cyclohexane using temperature change. When polyisobutylene was used, there was low aggregation and the surface of the product was smooth and had a few pores. The dissolution of the drug was altered by the core to wall ratio. The microcapsules were also treated with spermaceti, which reduced the rate of release of the drug; the release was also influenced by the amount of sealant used and the particle size of the product.

Chemtob etal. (1989) investigated the influence of polyisobutylene on the microencapsulation of metronidazole by dissolving ethylcellulose in cyclohexane at 80°C and cooling. The molecular weights of polyisobutylene used were 3.8 x 105 and 1.12 x 106. As the concentration of polyisobutylene is increased, aggregation is minimized and spherical microcapsules are obtained. At high concentrations of polyisobutylene some empty microcapsules are formed; this was also noted by Benita and Donbrow (1982). At a concentration of 3%, the higher molecular weight polyisobutylene gave less aggregation, similar to that reported by Koida etal. (1983). The percentage of the sieve fraction <315 nm is generally increased when polyisobutylene is added during the preparation of the microcapsules. It was found that the total drug content was not generally influenced by the addition of the polyisobutylene. It was noted that the times for 50% of the drug to be released at a pH of 1.2 and 37°C decreased as the concentration of polyisobutylene with the lower molecular weight increases at a core to wall ratio of 1 to 1, but not at a ratio of 2 to 1. When polyisobutylene with a higher molecular weight was used T50% varied with polyisobutylene concentration.

Piroxicam microcapsules were prepared by coacervation using ethylcel-lulose. It was found that it took 240 min to release 63% of the drug from microcapsules, compared with 6.9 min for the drug in hard gelatin capsules (Bergisadi and Gurvardar, 1989).

Dubernet etal. (1991) prepared microcapsules of ibuprofen with ethylcellulose dissolved in methylene chloride. Methylcellulose or polyvinyl alcohol, as the emulsifying agent, was dissolved in water and then the polymer solution containing the drug was added, an emulsion formed and evaporation proceeded until all the solvent was lost. In addition to the above procedure the crystal window concept was used in which the solvent evaporation is interrupted and the supernatant removed to prevent crystallization in the aqueous phase. This tends to remove drug molecules and prevent deposition. However, crystal formation was in some cases observed in both systems. Based on altering the drug concentration in both the aqueous and non-aqueous phases and the nature of the emulsifier, a mechanism for crystal deposition is proposed which involves the formation of nuclei in the unstirred layer surrounding the emulsified droplet during solvent evaporation. Crystal growth is also controlled by the drug concentration in both phases and the viscosity of the polymer layer at the interface.

Propranolol hydrochloride microcapsules were prepared by solvent evaporation by dissolving ethylcellulose in acetone and adding the dispersion to liquid paraffin by Ku and Kang (1991). The amounts of drug dissolved at pH 1.2 in aqueous solution increased as the drug content of the microcapsules increased and the dissolution was not affected by the concentration of sorbitan tristearate in the microencapsulation process.

Bacampicillin was encapsulated with different viscosity grades of ethylcellulose dissolved in cyclohexane, employing polyisobutylene with different molecular weights (Oppanol B200, B100, B50, B3) as the coacervation-inducing agent (Kristl etal., 1991). It was found that when polyisobutylene of low molecular weight was used agglomerates are formed as a result of large coacervate droplet size and low viscosity of the continuous phase. If a high molecular weight of polyisobutylene is used, much of the ethylcellulose was not used for wall formation. Further experiments were carried out with Oppanol 50, and different organic liquids were used for washing purposes. It was found that a non-agglomerated, free-flowing product was obtained when n-heptane was used, in contrast to some agglomeration obtained when petroleum ether or cyclohexane were used. Different celluloses and different core to wall ratios influence the shape of the microcapsules. Usually, spherical and small microcapsules were obtained using ethylcellulose N-50 with a core to wall ratio of 1:1.5. Stability studies showed that most of the original drug was retained. A kinetic analysis of the release of the drug was carried out. It was found that a combined zero-and first-order kinetic relationship was most suitable. The drug release decreased with increasing molecular weight to a minimum when the molecular weight of ethylcellulose was approximately 13 x 104, depending upon the polyisobutylene used, then the rate of release increased with increasing molecular weight of ethylcellulose.

Chloroquine phosphate and quinine hydrochloride microcapsules have been prepared by a thermally induced coacervation method using ethylcellulose. The microencapsulation process masked the taste of the drug and dissolution studies showed a prolonged release profile. Tablets of the microencapsulated drug were also prepared and tested (Chukwu etal., 1991).

Sveinsson and Kristmundsdottir (1992) encapsulated naproxen by coacervation-phase separation from a warm solution of ethylcellulose. The product after cooling was washed with cyclohexane and dried. The core to wall ratio was 1:1 or 1:2 and polyisobutylene concentrations ranged from 0 to 8%. It was found that an increase in the speed of stirring produced a greater proportion of smaller microcapsules, but dissolution characteristics and drug loading remained unaffected. Results of the sieving analysis indicated that the presence of polyisobutylene resulted in a pronounced decrease in the size of the microcapsules at both core to wall ratios. On increasing the concentration of polyisobutylene, the surface of the microcapsule became smooth and compact, but the shape remained irregular. The microcapsules were composed of aggregates of individually coated particles. The time for 50% of the drug to be released at a pH of 7.5 decreased from 140 min for 0% polyisobutylene to 20 min for 6% polyisobutylene when the core to wall ratio was 2:1.

Indomethacin was encapsulated with ethylcellulose by complex emulsifi-cation. By altering the core to coat ratio, the size range of microcapsules, or by incorporating a channelling agent such as PEG 4000 the drug release rate can be controlled (Jani etal., 1992).

Puglisi etal. (1992) prepared microspheres of tolmetin by cooling a solution of ethylcellulose containing polyisobutylene or ethylene vinyl acetate copolymer. The presence of the coacervating agent did not appreciably influence the drug content or the wall thickness, but did increase the particle size, especially when polyisobutylene was added. Coacervation with either agent produced a smooth surface and fewer holes were observed with ethylene vinyl acetate, by both scanning electron microscopy and fluorescent microscopy. Dissolution studies were carried out at 37°C at pH 7.4 and 4 in aqueous medium and also in the presence of Tween 20. In all cases the encapsulated drug delayed the release. Gastric lesions produced by a tolmetin preparation in rabbits were reduced when the drug was encapsulated; this was attributed to a shorter contact time with the gastric mucosa. A decrease in body temperature effected by the drug and the encapsulated drug with or without a coacervating inducing agent was similar.

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