Formulation and Manufacture of Pharmaceuticals by Fluidized-Bed Impregnation of Active Pharmaceutical Ingredients onto Porous Carriers

摘要

A manufacturing method is presented for solid dosage forms using fluidized-bed impregnation, which could eliminate many of the challenges during solid dosage manufacturing. The main difference between impregnation and dry blending is the placement of the active pharmaceutical ingredient (API) inside a porous carrier. This makes the final material flow properties independent of the physical properties of the API. The method consists of spraying an API solution in appropriate solvent onto a carefully chosen porous excipient in a fluidized state. The solution penetrates the porous carrier due to capillary forces and the solvent is evaporated soon after that. Impregnation and drying occur simultaneously, which makes this impregnation method suitable for continuous implementation. Carefully choosing the operating conditions allows impregnation to occur without introducing spray drying or spray coating of the API. The method is shown to generate an impregnated excipient with very high degree of homogeneity independent of the API loading. It is also shown that mild milling further improves blend uniformity to RSD levels below 1%, which are challenging to achieve using conventional techniques. On impregnation, the final physical properties of the material are seen to be mainly unchanged from the initial excipient properties. A study of this one-step manufacturing method is described, using acetaminophen as the model drug and anhydrous calcium phosphate dibasic as the porous excipient. The experimental work presented establishes a proof of concept and investigates in detail blend uniformity, physical state of impregnated API, final physical properties of impregnated material, compressibility during tableting, capsule filling, and release profile of the final capsule formulation. It also discusses potential ways for drug release control and improvements using impregnation.