Manufacturing of Pharmaceuticals by Impregnation of an Active Pharmaceutical Ingredient onto a Mesoporous Carrier: Impact of Solvent and Loading

Abstract

In this study, an active pharmaceutical ingredient (API) was impregnated onto a mesoporous carrier (excipient) in a fluidized bed. Impregnating APIs in porous carriers has the potential to simplify the drug substance development process and leads to the elimination of the blending and granulation unit operations. Impregnation and drying occur simultaneously in fluidized-bed impregnation, and this method precludes several challenges encountered in other impregnation methods. Furthermore, the process ensures a uniform distribution of APIs within the porous carriers. This method also allows for a variety of solvents to be used in the impregnation. Using a batch fluidized-bed dryer, impregnation of acetaminophen (APAP) onto a magnesium/aluminum metasilicate (Neusilin R) was studied. Water and methanol were used as transport solvents to impregnate different loadings (w/w) of APAP, namely, ranging from 24 to 0.1%. Uniformity tests indicated that APAP loadings of all impregnated products are close to their target loadings across carrier size classes. Tests before and after impregnation showed that there were no changes observed in the physical properties of the carrier, such as particle size, compressibility, and flow properties. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) analysis performed on the samples indicated that the low loadings APAP was present in the carrier pores in its amorphous state. At high loadings, we observed that APAP was mainly present in its amorphous state, however, some degree of crystallinity was observed. Lastly, dissolution tests on the impregnated product showed enhanced dissolution rates in acidic media, and comparable dissolution rate in de-ionized (DI) water, compared to the pure drug crystals. Our results show that the method of fluidized-bed impregnation yields a product with high uniformity and overcomes several challenges presented by traditional physical blends.