HUNDREDS OF DIFFERENT methods exist for making microcapsules of varying sizes and compositions. The choice is governed by the substance being encapsulated, the coating material, the intended use, and economic and quality-control factors, among others. To illustrate some general principles of the technology, here is a description of one process that is used to microencapsulate ibuprofen. It was developed by Sambasiva Rao Ghanta and Robert Edmon Guisinger of Eurand America, Inc., in Vandalia, Ohio, and is set forth in full in U.S. Patent 5,653,993.
The procedure starts with an aqueous solution of the first constituent of the capsule shell, a chemically modified form of cellulose called cellulose acetate phthalate (CAP). Sodium bicarbonate is added to make the powdered CAP more soluble, and the solution is agitated with a turbine stirrer in a container equipped with baffles on the sides. It may take several hours to get all the CAP to dissolve.
Solid, finely milled ibuprofen powder, in grains 25 to 500 microns in diameter, is then added to the mixture, along with a small amount of a nontoxic detergent such as sodium lauryl sulfate to help keep it in suspension. A separately prepared aqueous solution of gelatin, the other capsule-wall constituent, is then added to the mixture. By using two wall constituents, the process combines the advantages and cancels the disadvantages of both: CAP is good at masking taste but dissolves slowly in the stomach, while gelatin has the opposite set of properties.
A very concentrated solution (26 percent) of sodium sulfate is now slowly run into the mixture of capsule-wall material and ibuprofen particles, which con- tinues to be stirred vigorously. The solubility of CAP and gelatin decreases as the sodium sulfate concentration increases. In the absence of stirring, a separate layer, formed mainly of a solution of those two ingredients, would form. With stirring, the strong shearing action imparted by the mixer and baffles causes the coating materials to adhere to the suspended ibuprofen particles. We now have rudimentary ibuprofencontaining microcapsules coated in a mixture of CAP and gelatin.
If left at this stage, the coating would simply wash off in the rinsing step. Converting the raw coat into a durable capsule wall involves some fairly straightforward chemistry. This relies on the fact that gelatin, like all proteins, is made up of long chains of amino acids. These chains contain a fair number of free amino groups, which can form strong bonds with aldehydes. The key step in stabilizing the product involves reacting the amino groups in the chains with a chemical that has the equivalent of two hooks, glutaraldehyde (OHCC 3 H 6 CHO). This connects adjacent chains in the gelatin with chemical bonds to form a strong threedimensional cross-linked network. The cross-linking reaction takes place in a mixture that has been cooled to room temperature from the elevated temperatures needed to dissolve the gelatin.
Finally, citric acid is added, causing the microcapsules to precipitate. They contain more than 80 percent ibuprofen by weight. The tiny beads are collected, either by filtration or with a centrifuge, washed with water, and dried. For consumer use, they can be pressed into tablets with a starch vehicle or encased in a swallowable capsule.—
D.L.
