Fenamate Cocrystals with 4,4′-Bipyridine: Structural and Thermodynamic Aspects

Cocrystallization
of nonsteroidal anti-inflammatory drug fenamates (N-phenylanthranilic acid (N-PA), niflumic acid0 (NFA), flufenamic
acid (FFA), tolfenamic (TFA) and mefenamic acids (MFA)) with 4,4′-bipyridine
(BP) has resulted in the formation of cocrystals with a 2:1 molar
ratio. Crystal Packing Similarity analysis has revealed that the packing
arrangement of the [N-PA+BP], [TFA+BP], and [MFA+BP] cocrystals consists
of discrete fragments of the crystal structures of initial APIs connected
to each other by BP molecules. In the case of [FFA+BP], the cocrystal
contains a previously unseen packing arrangement of FFA molecules
which may be a fragment of a new polymorphic FFA form. Differential
scanning calorimetry studies show a good correlation between the cocrystal
melting temperature and the melting points of the corresponding pure
APIs. The enthalpies of cocrystal formation are small, which indicates
that the packing energy gain only originates from weak van der Waals
interactions between the API and BP molecules.

非甾体抗炎药芬那酸类药物——包含N-苯基邻氨基苯甲酸（N-phenylanthranilic acid, N-PA）、尼氟酸（niflumic acid, NFA）、氟芬那酸（flufenamic acid, FFA）、托芬那酸（tolfenamic, TFA）与甲芬那酸（mefenamic acids, MFA）——与4,4'-联吡啶（4,4′-bipyridine, BP）的共结晶反应，成功得到摩尔比为2:1的共晶产物。晶体堆积相似性分析结果表明，[N-PA+BP]、[TFA+BP]及[MFA+BP]三种共晶的堆积结构，由初始活性药物成分的晶体结构离散片段通过BP分子相互连接而成。针对[FFA+BP]共晶，其内部氟芬那酸分子呈现了此前未被观测到的堆积排布，该排布可能属于一种新型多晶型氟芬那酸的结构片段。差示扫描量热法研究显示，共晶熔融温度与对应纯活性药物成分的熔点之间具有良好的相关性。共晶形成焓数值较小，表明体系的堆积能量增益仅来源于活性药物成分与BP分子间的弱范德华相互作用。