Addition of a miscible liquid, a non-solvent for the polymer
When ethanol is added to an aqueous solution of gelatin, there is a competition for the water molecules, and some of the water is removed from the gelatin. The partially dehydrated polymer begins to aggregate and a phase rich in gelatin, the coacervate, separates from solution. The addition of excess ethanol causes the formation of a gelatinous mass which is not satisfactory for microencapsulation. As ethanol is added, the coacervate is formed and tends to envelop water-insoluble powders or liquids. Phase diagrams are useful to describe the appropriate concentrations to select for coacervation (Kondo, 1979a, Deasy, 1984a).
As an example, rose oil has been encapsulated by this process above room temperature. A limited amount of ethanol was added, and the temperature was decreased to harden the gelatin microcapsules. After separation the microcapsules were washed with ethanol and dried. A number of polymers other than gelatin may be used, such as agar, pectin, methylcellulose and polyvinyl alcohol, and a number of other hydrophilic organic liquids have been employed - namely acetone, dioxane, isopropanol (Kondo, 1979a). Other modifications of this method include temperature control, pH adjustment and hardening with formalin (Khalil et al., 1968; Nixon et al., 1968). The core material to be encapsulated should have a low solubility in water in order to obtain an appropriate yield of product and may be either liquid or solid.
A useful development of this process is the formation of nanoparticles which are so named because their size is in the nanometer range. Because of their small size, they may be considered as useful drug delivery devices for parenteral purposes. The preparation of nanoparticles involves the treatment of a solution of gelatin containing a suitable surfactant, at appropriate temperature and pH with ethanol, so that the coacervate region is just reached, as indicated by an increase in turbidity. The coacervate is redissolved so that the molecules exist in the 'rolling up region'. To prevent aggregation of the nanoparticles, the mixture is homogenized. The rolled up gelatin can entrap the core material and then the nanoparticles are hardened with an agent such as glutaraldehyde (Marty etal., 1978; Kreuter, 1978).
Gelatin and other hydrophilic colloids may be treated with various salts such as sodium sulfate which tend to desolvate the colloid, effecting coacervation. This process tends to require a high concentration of salt, 20-30%, which should be removed by treatment with water. Salts with different water-binding capacity according to the Hofmeister series may be used. It is usually necessary to harden the microcapsules by temperature change, pH adjustment or treatment with formaldehyde to obtain a satisfactory product (Khalil etal., 1968; Deasy, 1984a).
It has been indicated in a number of reviews that temperature change will promote coacervation-phase separation (Madan, 1978; Sparks 1984). The phase separation is believed to be brought about as a result of a decrease in solubility of the polymer. Thus, a decrease in temperature will promote phase separation of gelatin from solution while an increase of temperature will effect a phase separation for methylcellulose, ethyl hydroxyethylcel-lulose and hydroxy propylcellulose (Sparks, 1984).
Temperature change is more often used in conjunction with other phy-sicochemical factors such as the use of non-solvents and pH adjustment to effect the appropriate coacervation condition. For example, a dispersion of a drug, aspirin, in gelatin was added to mineral oil then phase separation was promoted by a reduction in temperature then isopropyl alcohol was added and the product was hardened with formaldehyde (Paradissis and Parrott, 1968).
Addition of an incompatible or non-wall-forming polymer
The addition of a polymer which has a high affinity for water has been used to induce coacervation-phase separation of the coating polymer, gelatin. Thus, a core was incorporated in a gelatin solution containing 10 to 25% polyethylene glycol to cause phase separation (Kondo, 1979a). Starch has also been noted to induce phase separation when gelatin is used as the wall-forming material (Madan, 1978). A low concentration of the non-wall-forming polymer may also aid in the control of the viscosity of the solution.
There are a number of polymers which are soluble in water and which possess either or both acidic and basic groups in their structure. Thus, an alteration of the pH causes a change in the ionization of the polymer, leading to insolubility. This effects a phase change and under the appropriate conditions, cores, either liquid or solid, suspended in the polymer solution can be encapsulated when the pH is adjusted. The polymer solution containing the suspended core is allowed to drop into a buffered solution and encapsulation takes place; alternatively, the pH of the aqueous polymer solution containing core is slowly changed. The water-insoluble drug sulfadiazine was encapsulated by permitting an alkaline solution of cellulose acetate phthalate containing the drug to drop into a solution of acetic acid (Milovanovic and Nairn, 1986).
A number of polymers such as casein, phthalylated gelatin, a copolymer of methacrylic acid and methylacrylate have been used to encapsulate various core materials such as photographic materials, solvents and oils.
Cores of biologically active cells in a suspension of a sodium alginate have been encapsulated successfully by permitting the mixture to flow dropwise into a dilute solution of CaCl2. The calcium ions caused immediate gelling of each droplet. The microcapsules were collected and subsequently treated with a polylysine solution to provide a permanent, semi-permeable membrane. In this process the calcium ions react with the alginate ions to produce a colloid-rich phase entrapping the core material (Lim and Moss, 1981).
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