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

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.

本研究报道了抗精神病药物加巴喷丁与间苯二甲酸、邻苯二甲酸、L-谷氨酰胺、对苯二甲酸及均苯三甲酸形成的5种新型多组分晶型，并通过X射线粉末衍射（X-ray Powder Diffraction，XRPD）对其进行了表征。尽管前三种复合物的单晶结构未能成功解析，但后两种晶型进一步通过单晶X射线衍射（Single Crystal X-ray Diffraction，SCXRD）、差示扫描量热法（Differential Scanning Calorimetry，DSC）、热重分析（Thermogravimetric Analysis，TGA）、热台显微镜（Hot Stage Microscopy，HSM）及红外光谱（Infrared Spectroscopy，IR）完成了表征。分别存在于羧酸与加巴喷丁中的强同聚型R22(8)与异聚型R42(8)合成子（synthon）遭到破坏，而在与均苯三甲酸、对苯二甲酸所形成的新型晶体结构中，形成了基于羧基···羧酸根与氨基···羧酸根相互作用的竞争性合成子。本研究还对这两种新型晶型的pH依赖性稳定性展开了探究，结果显示与均苯三甲酸形成的共晶以及与对苯二甲酸形成的分子盐的稳定性存在显著差异，其中该分子盐的稳定pH范围相对更窄。此外，在研究高度难溶性化合物时，机械化学被证实是相较于传统溶液合成法更具优势的替代方案。