National Engineering Research Center of Industrial Crystallization Technology, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, People's Republic of China.
Collaborative Innovation Center of Chemical Science and Engineering, Tianjin, 300072, People's Republic of China.
Pharm Res. 2024 Aug;41(8):1737-1754. doi: 10.1007/s11095-024-03748-5. Epub 2024 Jul 29.
The primary problem with climbazole (CLB), a broad-spectrum imidazole antifungal drug, is its low water solubility. In order to increase its water solubility and antifungal activity, three new multi-component crystals were synthesized in this work, and the intermolecular interactions were systematically studied. This work helps to optimize the CLB product formulation and extend its application prospects.
In this work, three novel multi-component crystals, CLB-malonic acid (CLB-MA) salt, CLB-succinic acid (CLB-SA) cocrystal and CLB-adipic acid (CLB-AA) cocrystal, were successfully synthesized. And the crystal structure, thermodynamic properties, solubility, dissolution, hygroscopicity, and antifungal activity of the three multi-component crystals were fully characterized by single-crystal X-ray diffraction (SCXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), dynamic water vapor adsorption (DVS) and powder dissolution tests, etc. The molecular interactions and molecular stacking in multi-component crystals were studied by Hirshfeld surface (HS), molecular surface electrostatic potential (MEP), interaction region indication (IRI) and atom and molecule (AIM) techniques.
The results show that the three multi-component crystals have good moisture resistance stability, and their water solubility is 6-22 times that of pure CLB. Meanwhile, the measurement of the minimum inhibitory concentration (MIC) proves that the cocrystal/salt has a stronger antifungal activity than climbazole. Quantum chemistry calculations of crystal structure visualized and quantified the interactions that exist in multi-component crystals, and explored the microscopic mechanisms underlying the different performance of multi-component crystals.
广谱咪唑类抗真菌药物克霉唑（CLB）的主要问题是其水溶性低。为了提高其水溶性和抗真菌活性，本工作合成了三种新的多组分晶体，并系统研究了它们的分子间相互作用。这项工作有助于优化 CLB 产品配方并拓展其应用前景。
本工作成功合成了三种新型多组分晶体，即 CLB-丙二酸（CLB-MA）盐、CLB-琥珀酸（CLB-SA）共晶和 CLB-己二酸（CLB-AA）共晶。通过单晶 X 射线衍射（SCXRD）、热重分析（TGA）、差示扫描量热法（DSC）、动态水汽吸附（DVS）和粉末溶解试验等手段对三种多组分晶体的晶体结构、热力学性质、溶解度、溶解、吸湿性和抗真菌活性进行了全面表征。通过 Hirshfeld 表面（HS）、分子表面静电势（MEP）、相互作用区域指示（IRI）和原子和分子（AIM）技术研究了多组分晶体中的分子相互作用和分子堆积。
结果表明，三种多组分晶体具有良好的耐湿性稳定性，其水溶解度是纯 CLB 的 6-22 倍。同时，最低抑菌浓度（MIC）的测定证明了共晶/盐比克霉唑具有更强的抗真菌活性。晶体结构的量子化学计算可视化和量化了存在于多组分晶体中的相互作用，探索了多组分晶体不同性能的微观机制。
