Cocrystals of Fenamic Acids with Nicotinamide

Cocrystal formation between nicotinamide and five fenamic acid derivative drugs (flufenamic acid, niflumic acid, tolfenamic acid, mefenamic acid and meclofenamic acid) was investigated using solution-based and solid-state preparation methods. It was anticipated that the well-known acid–aromatic nitrogen heterosynthon would provide a sufficient driving force for cocrystallization. The experiments yielded cocrystals with four of the five acids. Although the structures of these molecules are similar, they showed marked differences in both the stability and the stoichiometry of the cocrystals. A detailed analysis of the structures and properties of both the starting materials and the cocrystals allows a tentative explanation of these differences, but it also shows that even though all four cocrystals utilize one of the most predictable supramolecular synthons (COOH···N), their structures and properties remain elusive to design.本研究采用溶液法与固相制备法，探究了烟酰胺（nicotinamide）与五种芬那酸衍生物类药物——氟芬那酸（flufenamic acid）、尼氟灭酸（niflumic acid）、托芬那酸（tolfenamic acid）、甲芬那酸（mefenamic acid）及甲氯芬那酸（meclofenamic acid）之间的共晶（cocrystal）形成行为。研究人员预期，广为人知的酸-芳族氮杂超分子合成子（acid–aromatic nitrogen heterosynthon）可为共晶结晶提供充足的驱动力。实验结果显示，五种芬那酸中有四种成功制备得到共晶产物。尽管这些药物分子的结构相近，但所得共晶的稳定性与化学计量比均呈现出显著差异。对原料与共晶的结构及性质开展详细分析后，可对上述差异给出初步解释，但同时也表明，即便这四种共晶均采用了最具可预测性的超分子合成子（supramolecular synthon）之一（COOH···N），其结构与性质依然难以通过设计实现精准调控。