Preparation of amorphous solid dispersions by cryomilling: chemical and physical concerns related to APIs and carriers

In this work, a chemical and physical evaluation of cryogenic milling to manufacture amorphous solid dispersions (ASDs) is provided to support novel mechanistic insights in the cryomilling process. Cryogenic milling devices are considered as reactors in which both physical transitions (reduction in crystallite size, polymorphic transformations, accumulation of crystallite defects and partial or complete amorphization) and chemical reactions (chemical decomposition, …) can be mechanically triggered. In-depth characterization of API- (content determination) and polymer- (viscosity, molecular weight, dynamic vapor sorption, Fourier transform infrared spectroscopy, dynamic light scattering and ANS and Th-T staining) chemical decomposition demonstrated APIs to be more prone to chemical degradation in case of presence of polymer. A significant reduction of the polymer chain length was observed and in case of BSA denaturation/aggregation occurred. Hence, mechanochemical activation process(es) for amorphization a...