Surov Artem O, Ramazanova Anna G, Voronin Alexander P, Drozd Ksenia V, Churakov Andrei V, Perlovich German L
G.A. Krestov Institute of Solution Chemistry RAS, 153045 Ivanovo, Russia.
Institute of General and Inorganic Chemistry RAS, Leninsky Prosp. 31, 119991 Moscow, Russia.
Pharmaceutics. 2023 Mar 3;15(3):836. doi: 10.3390/pharmaceutics15030836.
In this study, the existing set of carbamazepine (CBZ) cocrystals was extended through the successful combination of the drug with the positional isomers of acetamidobenzoic acid. The structural and energetic features of the CBZ cocrystals with 3- and 4-acetamidobenzoic acids were elucidated via single-crystal X-ray diffraction followed by QTAIMC analysis. The ability of three fundamentally different virtual screening methods to predict the correct cocrystallization outcome for CBZ was assessed based on the new experimental results obtained in this study and data available in the literature. It was found that the hydrogen bond propensity model performed the worst in distinguishing positive and negative results of CBZ cocrystallization experiments with 87 coformers, attaining an accuracy value lower than random guessing. The method that utilizes molecular electrostatic potential maps and the machine learning approach named CCGNet exhibited comparable results in terms of prediction metrics, albeit the latter resulted in superior specificity and overall accuracy while requiring no time-consuming DFT computations. In addition, formation thermodynamic parameters for the newly obtained CBZ cocrystals with 3- and 4-acetamidobenzoic acids were evaluated using temperature dependences of the cocrystallization Gibbs energy. The cocrystallization reactions between CBZ and the selected coformers were found to be enthalpy-driven, with entropy terms being statistically different from zero. The observed difference in dissolution behavior of the cocrystals in aqueous media was thought to be caused by variations in their thermodynamic stability.
在本研究中，通过将卡马西平（CBZ）与乙酰氨基苯甲酸的位置异构体成功结合，扩展了现有的卡马西平共晶体集合。通过单晶X射线衍射，随后进行QTAIMC分析，阐明了CBZ与3 - 和4 - 乙酰氨基苯甲酸共晶体的结构和能量特征。基于本研究获得的新实验结果和文献中的可用数据，评估了三种根本不同的虚拟筛选方法预测CBZ正确共结晶结果的能力。结果发现，氢键倾向模型在区分CBZ与87种共形成物共结晶实验的阳性和阴性结果方面表现最差，其准确率低于随机猜测。利用分子静电势图的方法和名为CCGNet的机器学习方法在预测指标方面表现出可比的结果，尽管后者具有更高的特异性和总体准确率，且无需耗时的密度泛函理论计算。此外，利用共结晶吉布斯自由能的温度依赖性，评估了新获得的CBZ与3 - 和4 - 乙酰氨基苯甲酸共晶体的形成热力学参数。发现CBZ与选定共形成物之间的共结晶反应是由焓驱动的，熵项在统计上不为零。共晶体在水性介质中溶解行为的观察差异被认为是由其热力学稳定性的变化引起的。
