Synthesis, characterization and structure–activity relationship of novel pregabalin cocrystals with sustained-release performance

Abstract

Pregabalin, as an analgesic drug, can treat epilepsy and neuropathic pain. However, it suffers from short half-life and rapid metabolism. In this work, a crystal engineering strategy was employed to regulate its drug release kinetics. Through integrated computational modeling and experimental synthesis, two novel pregabalin cocrystals with p-methylbenzoic acid and vanillic acid were developed. The cocrystal with cinnamic acid, although previously reported, was also included in this study with a newly developed synthetic route and a comprehensive mechanistic investigation. The cocrystal formation and crystal packing were systematically characterized by PXRD, SCXRD, TG/DSC, IR, Raman, and ¹H NMR. Stability tests indicate good hygroscopic and enhanced stability, while solubility and dissolution experiments showed reduced solubility and dissolution rates, with the IDR decreasing by 59.6–85.3%. Based on quantum chemical calculations and experimental evaluations, a comprehensive sustained-release mechanism of the cocrystals was proposed, which includes reduced solvation capacity at the cocrystal surface, the formation of an internal hydrophobic network, and a higher energy barrier required to disrupt the cocrystal architecture. This study effectively mitigates the pharmacokinetic limitations of pregabalin, offering a new research paradigm for the design and development of sustained-release drugs.