Gelatin

Phares and Sperandio (1964) showed that a number of insoluble particles, liquids and solids, could be encapsulated with gelatin using sodium sulfate as the coacervation-inducing agent. A phase diagram for the system gelatin, water and sodium sulfate was prepared to show the region of encapsulation.

As a result of the preparation of phase diagrams (Nixon etal., 1966), suitable compositions within the coacervate region were selected for preparing microcapsules. Subsequently, an improved method for preparing microcapsules by simple coacervation methods using gelatin was accomplished by Nixon etal. (1968). The drug, sulfamerazine, was dispersed in either ethanol or 20% w/w sodium sulfate and added to the isoelectric gelatin solution. The mixture was stirred and maintained at 40°C. Both lime-pretreated and acid-processed gelatin were studied. After further treatment with the coacervating agent, the product was washed with isopropanol and hardened with a formalin-isopropanol mixture. This method produced the best results. In an alternative procedure for hardening the microcapsule, the product was cooled to 5 or 10°C, washed and dried; this method produced a cake. In a third method, the microcapsules were spray dried, but the product was not satisfactory because most of the drug was not encapsulated. The size of the drug particles to be coated did not hinder the coacer-vation process. It was found that encapsulation was successful if the drug particles were dispersed in the gelatin solution before coacervation or added to the system when coacervation was complete. The authors suggested that encapsulation can occur by two methods: the dispersed particles functioning as nuclei around which the coacervate drops form, or the coacérvate droplets surround the drug particles. The recovery of the microcapsules was based on hardening the coacervate shell by dehydration. Isopropanol with its milder dehydrating effect compared with ethanol was more appropriate. The release rate of the drug was decreased with longer formalization time or thicker walls. Microcapsules prepared using ethanol provided a slower release than when they were prepared with sodium sulfate, which results in a more porous coat because of the salt's ability to hinder the hardening effect of isopropanol.

Nixon and Matthews (1976) made gelatin microcapsules by preparing a 5% solution of the polymer at 40°C and adding the coacervating agent, either 20% sodium sulfate or absolute ethanol. The core was added to some of the coacervating liquid and dispersed by ultrasonic vibration. The coacervate wall was then gelled by using a 30% ethanol in water or a 7% solution of sodium sulfate in water at a temperature below the gelling temperature of the coacervate; that is, below 12°C. Partial dehydration was accomplished by using two washes of isopropanol, a final wash with ethanol and finally heating the microcapsules to less than 60°C. The product was examined using a scanning electron microscope. Microcapsules produced by using either ethanol or sodium sulfate had no cracks or fissures. The surface of microcapsules produced using ethanol were smoother than those produced using Na2S04. Surface folding of the ethanol-treated microcapsules was common and is associated with the formation of vacuoles within the alcohol coacervate droplets. The authors suggest that during recovery the vacuoles collapse and the wall material folds in on itself. Crystalline deposits on the surface of sodium sulfate-produced microcapsules were that of the salt. The authors suggest that microcapsules prepared by coacervation are formed by a process that involves the combination of several smaller microcapsules.

Water in oil emulsions have been encapsulated by gelatin using the coacervation process. For example, a concentrated solution of urea in water was prepared as a w/o emulsion with corn oil and hydrogenated castor oil. A solution of gelatin and the above emulsion were heated to 40°C and dispersed slowly in a stream into a solution of sodium sulfate at 40° C with stirring. After phase separation, the mixture was cooled, adjusted to pH 9.5 and treated with formaldehyde to harden the product (Heistand etal., 1970).

The effect of ethanol, sodium sulfate and resorcinol on the induction period and some physical properties of gelatin coacervates has been studied by Zholbolsynova etal. (1971). Later Zholbosynova etal. (1988) investigated the influence of alcohol on the rheological properties of aqueous solutions of gelatin during the formation of coacervates. It was found that the viscosity of the coacervates increased with increasing concentration of the alcohol in the order methyl alcohol < ethyl alcohol < propyl alcohol. The strength of the coacervates prepared with ethanol as the coacervation agent increased with time, and was at maximum at an ethanol concentration of 13% v/v.

Nath (1973) investigated the influence of coacervation volume as altered by the temperature and the coacervating agent. It was found that as the temperature of coacervation increased in the system, gelatin, water, sodium sulfate, the volume of the coacervate increased. The volume decreased as the concentration of the coacervating agent, sodium sulfate, increased from 4.5 to 6.6%. The addition of hydrocolloid also altered the coacervation process. Dilute solutions 0.05-0.1% of carboxymethylcellulose reduced the growth of microcapsules during gelling. At higher concentrations, 0.1 to 1%, it increased the viscosity of the system. However, the capsules could not be filtered from the viscous liquid. The addition of polyvinyl pyrroli-done promotes flocculation and this interferes with coacervation.

Later, Nath and Shirwaiker (1977) studied the enhanced adsorption of atropine sulfate by kaolin in the presence of the coacervation-phase of gelatin, compared with either kaolin or the dried encapsulated form separately. The enhanced adsorption was attributed to the altered surface characteristics of the adsorbent in the gelatin-Na2S04 system. Release of the drug from the coacervated kaolin product into simulated gastric or pancreatic fluid in vitro was considerably slower than that from the other two forms.

Simple gelatin coacervate systems have been used to enhance drug uptake by adsorption. Nath and Borkar (1979) prepared gelatin coacervates using ethanol as the coacervating agent. In three separate experiments, the amount of amphetamine bound by kaolin, gelatin coacervate and the kaolin gelatin coacervate system was studied. The authors suggest that the enhanced uptake of the drug by the coacervated kaolin results from successive layers of the coacervate phase providing new surfaces for drug deposition. Drug release in gastric and pancreatic fluid from the kaolin gelatin product follows first-order kinetics. Addition of surfactant to the dissolution fluid, Tween 20, Tween 80 or sodium lauryl sulfate, enhances drug release, which suggests that the drug material is bound by both the core material and the coacervate coat.

Coacervation of gelatin in the presence of surface-active agents has been investigated for a number of reasons by Ohdaira and Ikeya (1973) and Ikeya etal. (1974a), who encapsulated lypophilic materials or water-insoluble substances using gelatin and a quarternary ammonium salt, e.g. octadecyl-trimethyl ammonium bromide. The microcapsules were hardened with formaldehyde in an alkaline solution to give independent microcapsules. Subsequently, Ikeya etal. (1974b) used an anionic surface-active agent, e.g. sodium lauryl sulfate, in the coacervation process to aid in the encapsulation of hydrophobic materials.

Two coacervate systems of gelatin-benzalkonium chloride and acacia-gelatin were prepared and analysed for the sorption of halothane. Significant halothane gas uptake was observed in the highly structured coacervate system (Stanaszek etal., 1974).

Coacervation of gelatin has been promoted by the addition of polyvinyl alcohol). The agglomeration of gelatin was attributed, by the authors Falyazi etal. (1975), to be the interaction of polyvinyl alcohol) and water, which alters the solubility of gelatin and promotes coacervation.

In order to improve its surface properties, pyrvinium pamoate was encapsulated with gelatin. Optimum results were obtained using a 10% gelatin solution at 50°C at a core to coat ratio of 2:1. Trivalent and divalent ions were effective in promoting coacervation when phase separation did not occur with NaCl. The addition of Tween 80 to the system before coacervation produced microcapsules that contained larger amounts of drug than when the surfactant was added after phase separation (Kassem et al., 1975a).

An inorganic polymer has been used to induce coacervation. Hoerger (1975) induced phase separation of gelatin using Calgon (sodium hexameta-phosphate) at 80°C using a lipophilic material as a core.

The stability of microencapsulated vitamin A and vitamin D concentrates in olive oil was not nearly as good as the non-encapsulated product stored under the same conditions, both in the presence of light and protected from light. It was suggested that the decreased stability was due to the porosity of the gelatin membrane which permitted light and moisture to reach the vitamins (Spiegl & Jasek, 1977).

Highly volatile liquids have been encapsulated with gelatin using sodium sulfate to effect coacervation. The microcapsules were then treated with isopropanol and formaldehyde. The product was further treated with stearic acid to prevent loss of the liquid cyclohexane. The microcapsules with a size range of 20-50 pim contain 75% of the volatile liquid (Spittler etal., 1977).

Coacervates of gelatin and benzalkonium chloride have been prepared from 10% and 5% solution, respectively, by Takruri etal. (1977). These coacervates were compared with organic solvents with regard to the partitioning of four barbiturate salts and also the absorption of the barbiturates in the rat colon. The authors suggest that coacervation systems form a more realistic model for studying the absorption characteristics of drugs than do conventional organic solvent-water systems.

Madan (1980) studied the release behaviour of microencapsulated clofibrate, a liquid hypercholesterolaemic agent and related the data to the formation of the microcapsules. The drug fell from a capillary tube into a stirred, warm solution of gelatin type B. Then a 20% solution of sodium sulfate was added to promote the coacervation of the oil droplets. The product was poured into a 7% solution of sodium sulfate to gel the wall. Chilled isopropanol was added to dehydrate and flocculate the coacervate drops. The microcapsules were then hardened by immersion in a 10% solution of formaldehyde for up to 8 h. The process produced discrete, free-flowing particles of a uniform size (190 ± 10 /tm). The dissolution of the microencapsulated drug in a 30% isopropanol solution at 37°C was studied. Several mathematical models were tested (square root, Langenbucher, cube root) but none yielded linear graphs. A close examination of the graphs showed four linear segments. The authors suggest that the matrix of the microcapsule differed from that proposed in the release of drug from solid matrices or from uniform non-disintegrating granules which tend to be homogeneous. The matrix appeared to be composed of various layers which exhibit different release characteristics.

The influence of glucose syrups and maltodextrin was studied by Marrs (1982). It was found that the inhibitory effect on gelation increases with the amount of high molecular weight oligosaccharides in the system. In addition, the properties of gelatin are modified by the composition of the starch hydrolysate.

Shchedrina etal. (1983) encapsulated dibunol by means of coacervation with gelatin solution. The stability of the microcapsules was investigated by determining such properties as bulk weight, friability and wearing properties after storage for 2.5 years at 20°C and 5°C. In vivo studies show the absorption of the oily drug was more uniform, continuous and prolonged compared with the oily liquid itself.

Nikolayev and Rao (1984) studied the effects of plasticizers on some physical properties of gelatin microcapsules prepared by coacervation. The microcapsules were prepared by treating a solution of gelatin at 50°C with a 20% solution of sodium sulfate. Oil coloured with Sudan III was added with stirring and the mixture cooled to 5°C to form the microcapsules. Microcapsules were also prepared by adding suitable amounts of plasticizer to the warm solution of gelatin prior to the addition of sodium sulfate. The resulting microcapsules were mono dispersed with a size range of 300-400/xm. The surface was smooth, the wall material was uniformly distributed and the coat on the plasticized microcapsule was thinner than on non-plasticized product. As the concentration of the plasticizer, glycerol, sorbitol, propylene glycol or polyethylene glycol 400 increased, the percentage of gelatin deposition decreased and there was also a tendency for a decrease in wall thickness. Finally, as the concentration of plasticizer glycerol or sorbitol was increased, the time for 50% release of the oil, as determined by dye concentration, decreased in a linear manner.

A matrix formulation of small particles, encapsulated with gelatin, has been prepared by decreasing the pH, causing the drug to precipitate from solution, and simultaneously effecting coacervation (Frank et al., 1985). Sodium sulfadiazine was encapsulated by this method by titrating a solution of the drug in water containing ethanol, sodium sulfate and gelatin with HC1. A white suspension of microencapsulated particles was formed, which was poured into cold Na2S04 solution and then stirred at the bath temperature to effect gelling of the liquid gelatin microcapsule shell.

A matrix encapsulation formulation of small particles of a water-insoluble drug, felodipine, was prepared by dissolving the drug in a little polyethylene glycol 400 and adding to the solution a 2.5% gelatin solution containing Na2S04 which caused precipitation of the drug and the formation of a coacervate around the fine drug particles. A solution of Na2S04 was added to complete the encapsulation; all steps were carried out at 55°C. The wall was gelled by pouring the suspension into a cold Na2S04 solution and hardened with formaldehyde (Brodin etal., 1986).

Gelatin coacervates have been prepared in the annulus between rotating concentric cylinders. Coacervation was induced in the water by the addition of Na2S04. The coacervate droplets showed a logarithmic, normal distribution and their size depended upon the rotation rate, residence time and pH (Yagi, 1986, 1987).

Coacervation and encapsulation of fat materials such as cosmetics using gelatin was achieved at 50°C, using a small quantity of sorbitol, effecting coacervation with carrageenan, followed by treatment with glutaraldehyde to form microcapsules. This product may then be treated with other polymers such as a mixture of polydimethylsiloxane and polyvinyl pyrrolidone) for printing on paper (Fellows etal., 1987).

Rozenblat etal. (1989) investigated the effect of electrolytes, stirring and surfactants in the coacervation and microencapsulation process using gelatin. Lime-pretreated bovine skin gelatin with a gel strength of 60 and 225 bloom and acid-processed porcine skin gelatin with gel strength of 175 and 300 bloom were used. The first step in the procedure was the addition of the core oleic acid and surfactant to an aqueous gelatin solution (8% w/v, pH 6.0-6.5) at 37°C, with stirring to effect emulsification. The second stage in the procedure was the encapsulation by adding a solution of 20% sodium sulfate. Finally a cool solution of sodium sulfate (7%) was added. The coacervation process was monitored by turbidity measurements. The microcapsules were observed and measured by using the microscope and a Coulter counter, or a computerized inspection system. It was found that coacervation is indifferent to the nature of the charge on the gelatin. However, an increase in bloom strength of the gelatin required smaller amounts of Na2S04. These findings support the theory of Nixon et al. (1968). Experiments using different electrolytes could be divided into three groups. A number of fluoride salts were used to induce phase separation, for example MgF2 and NaF. It was found that the effects of the electrolytes to induce phase separation increased with the charge density and the solubility of the electrolyte. The group was called phase separation inducers. Salts of polyvalent anions also belong in this class. A number of salts, e.g. NaN03 and Nal, require a greater amount of Na2S04 to induce phase separation; these monovalent salts are known as chaotropic salts and have the ability to destabilize membranes. They decrease the energy required for solubilization and therefore increase the solubility of the gelatin. The efficiency of the chaotropic salts as inhibitors of coacervation decreases with an increase in the charge density. The inert salts do not induce phase separation and do not change the solubility of the polymer in water. Their charge density is between the previous two groups. The authors were able to encapsulate oleic acid in the presence of positively charged gelatin, non-ionic surfactants and anionic surfactants, but not in the presence of a positively charged surfactant. The inability to coat the oil drops in the presence of a positively charged surfactant was attributed to electrostatic repulsion. Encapsulation of the oil was not successful with negatively charged gelatin, but it could be encapsulated in the presence of non-ionic surfactants except Tween 20. These results disagree with those of Siddiqui and Taylor (1983). The control of stirring speed is most important during the cooling stage of the process, as it determines the microcapsule size. Prolonged stirring at stage two tends to cause an increase in aggregation.

Microcapsules of cholecalciferol were prepared by both simple and complex coacervation using gelatin A and gelatin B. Research of Sawicka (1990) shows that the properties of the microcapsules depend upon the coat to core ratio regardless of the type of gelatin or the coacervating process used. The size of the microcapsules, their dissolution in digestive juice, the coat to core ratio, the core content, and the rate of drug release were determined. With simple and complex coacervation methods, the optimum coat to core ratios were 0.25:1 and 0.5:1, respectively.

Coacervation with gelatin has been used to encapsulate drugs with an unpleasant taste. Ozer and Hincal (1990) encapsulated beclamide by simple coacervation by adding the drug to a stirred solution of gelatin at 40°C. Sodium sulfate solution was added slowly over a 35 min period. After cooling, decantation and washing with water, the microcapsules were hardened by the addition of a 75% w/v potassium aluminium sulfate solution at pH 4 and 7°C. Several other hardening agents were employed: formaldehyde, glutaraldehyde and isopropanol-aldehyde solutions. In order to improve flow properties, some of the microcapsules were dispersed in isopropanol 50% at 4°C containing Aerosil. The addition of alcohol during the preparation extracted some of the active ingredient, resulting in decreased beclamide content. Glutaraldehyde was found to be the best hardening agent. Aerosil tended to prevent the microcapsules from sticking together, in contrast to isopropanol. The mean size of the drug particle was 127.5 (im and after microencapsulation the mean size was 550/xm. The authors investigated some of the properties of the microcapsules, namely flow, consolidation, and the apparent and tapped densities. The release rates of the drug were found to be dependent on the type of gelatin and the method of hardening. Microcapsules prepared with no hardening agent had the fastest rate of release, those hardened with glutaraldehyde had intermediate rates whereas those hardened with an aldehyde and isopropanol mixture had the slowest release rate. The authors also prepared three types of tablet formulations: conventional, chewable and effervescent. Physical properties and dissolution of the drug from the tablets were also studied.

Nikolaev (1990) found that the physicochemical properties of gelatin microcapsules prepared by coacervation depended upon the polymer: core ratio and the treatment with formaldehyde. The particle size and the specific surface area of the microcapsules were influenced by the formaldehyde treatment. Properties of the final product, which contained norsulfazole as the model drug, were also dependent on the polymer density, the bulk mass and thickness of the microcapsule coatings when the number of drug particles increased.

Gelatin has been used to encapsulate natural and partially synthetic oils. The method developed by Keipert and Melegari (1992) enabled the preparation of microparticles that were approximately spherical and had a particle size of about 100-600 fim. It was shown that pH, the type of gelatin and additives to the gelatin system influence the characteristics of the microparticles, such as the mean diameter and surface, through the effects of viscosity and interfacial tension. The quality of the microparticles is also influenced by the characteristics of the core liquid, particularly the amount of unsaturated fatty acid.

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