Green in situ co-amorphization strategy by introducing small molecular coformers: Mechanistic understanding and enhanced dissolution of ketoprofen with complexation

Abstract

Over the past half century, the dissolution of poorly water-soluble drugs has long been a major challenge in pharmaceutics. As in-depth research on amorphization strategies progresses, in situ amorphization has emerged as an effective solubilization approach, avoiding production and stability concerns of other methods. This study aimed to design in situ co-amorphous combinations of ketoprofen (KET) with small-molecule coformers (L-lysine, L-arginine, meglumine) and explore the mechanism of humidity-mediated in situ co-amorphization. When these combinations contacted water, gradual co-amorphization was confirmed by PLM, PXRD, DSC and FTIR analyses. Results indicated that such co-amorphization process was significantly affected by the molar ratio of components, ambient temperature and pH of aqueous media, which were related to intermolecular interactions, molecular motion and reaction microenvironment. Compared to crystalline KET, the three combinations showed 6.08–7.02 times increase in apparent solubility as well as 2318.81–3620.48 times improvement in intrinsic dissolution rate. Moreover, they sustained long-term supersaturation, attributed to complexation reaction of KET and coformer validated via phase solubility and nucleation inhibition tests. Overall, this study proposes an in situ co-amorphous combination strategy induced by humidity and reveals such amorphization mechanism, efficiently addressing the poor water solubility of drugs.