Synthesis, Characterization and structure-activity relationship of a novel pregabalin cocrystals with sustained-release performance

Abstract

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, crystal engineering strategy was employed to regulate the drug release kinetics of it. Through integrated computational modeling and experimental synthesis, two novel pregabalin cocrystals with p-methylbenzoic acid 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 IDR decreased by 59.6%-85.3%. Based on quantum chemical calculations and experimental evaluations, a comprehensive sustained-release mechanism of the cocrystals was proposed, which include 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 drug.