New Pharmaceutical Cocrystal Forms of Flurbiprofen: Structural, Physicochemical, and Thermodynamic Characterization
New Pharmaceutical Cocrystal Forms of Flurbiprofen: Structural, Physicochemical, and Thermodynamic Characterization
复制标题
DOI：
10.1021/acs.cgd.9b00781
复制
发表时间：
2019-10-01
影响因子：
3.8
通讯作者：
Perlovich, German L.
中科院分区：
文献类型：
--
作者：
Surov, Artem O.;Manin, Alex N.;Perlovich, German L.
在这项工作中，通过固液二元相图的热力学分析，发现了非甾体抗炎药氟比洛芬与水杨酰胺、苯甲酰胺和吡啶甲酰胺的三种新共晶，并通过高分辨率同步加速器粉末衍射数据确定了它们的晶体结构。已经进行了周期性密度泛函理论计算，以进一步了解共晶结构之间的能量差异。通过组分的共晶浓度检查了共晶的 pH 溶解度行为和溶解度优势，并且根据形成反应的吉布斯能合理化了不同固相之间的热力学稳定性关系。此外，基于药物和共形成物的实验固有溶解度并辅以计算的物理化学 HYBOT 描述符，提出了一种估计共晶溶解度积 (K-sp) 的新模型。观察并讨论了吉布斯自由能的变化与共晶形成的分子体积之间的关系。
In this work, three new cocrystals of the nonsteroidal anti-inflammatory drug flurbiprofen with salicylamide, benzamide, and picolinamide have been discovered using thermodynamic analysis of solid-liquid binary phase diagrams, and their crystal structures have been determined from the high-resolution synchrotron powder diffraction data. Periodic density functional theory calculations have been carried out to gain additional insight into energy differences between the cocrystal structures. The pH-solubility behavior and solubility advantage of the cocrystals have been examined via eutectic concentrations of the components, and the thermodynamic stability relationships between different solid phases have been rationalized in terms of Gibbs energies of the formation reactions. In addition, a new model has been proposed for estimating the solubility product (K-sp) of a cocrystal, based on the experimental intrinsic solubility of the drug and coformer complemented by calculated physicochemical HYBOT descriptors. The relationship between the change in Gibbs free energy and the molecular volume of cocrystal formation has been observed and discussed.