Co-amorphization for solubility and dissolution rate improvement: the case of low-crystallization-tendency drugs

Poor aqueous solubility and limited oral bioavailability remain major challenges in drug development. Although amorphous forms can improve solubility and dissolution, their physical stability is often compromised by recrystallization. Co-amorphous systems (CAMS) have therefore been extensively investigated as a strategy to stabilize amorphous drugs and enhance their performance. Nevertheless, compounds classified as Type III according to Baird et al. (2010) are generally considered good glass formers with inherently low recrystallization tendencies, raising questions regarding the necessity and additional benefits of CAMS for this type of compounds. This review aims to evaluate the relevance and effectiveness of CAMS for drug classified as good glass formers, with particular emphasis in their impact on solubility, dissolution behavior, and physical stability. Relevant publications were systematically identified through major scientific databases and search engines using keywords "co-amorphous system" and "coformer". A total of 18 studies involving Type III drugs were included and critically analyzed. Analysis of the included studies revealed that CAMS improved aqueous solubility by approximately 1.7-fold to more 3900-fold and significantly enhanced dissolution performance, with reported increases in dissolution parameters ranging from 1.75-fold to 255-fold. In addition, several formulations exhibited rapid and near complete drug release as well as prolonged physical stability of up to seven months. These effects were mainly driven by intermolecular interactions that suppressed recrystallization and enhanced supersaturation. Overall, CAMS improved solubility, dissolution, and physical stability, indicating benefits beyond amorphous stabilization even for good glass formers.