On the Track of New Multicomponent Gabapentin Crystal Forms: Synthon Competition and pH Stability

Abstract

Five new multicomponent crystal forms of the neuroleptic drug gabapentin with isophthalic acid, phthalic acid, l-glutamine, and terephthalic and trimesic acids have been reported and are characterized by XRPD. While the single crystal structures of the first three compounds were not possible to determine, the latter two are further characterized by SCXRD, DSC, TGA, HSM, and IR. The strong homomeric R22(8) and heteromeric R42(8) synthons observed in the carboxylic acids and gabapentin, respectively, were disrupted and competing synthons based on carboxyl···carboxylate and amine···carboxylate interactions formed in the new crystalline structures with trimesic and terephthalic acids. The pH dependent stability of these two new forms was also studied, and significant differences were found for the cocrystal with trimesic acid and the molecular salt with terephthalic acid, which is stable in quite a narrower pH range. Furthermore, mechanochemistry proved to be an advantageous alternative to traditional solution techniques when highly insoluble compounds are under study.