Wenxi Song, Na Wang, Ao Li, Xiongtao Ji, Xin Huang, Ting Wang, Hongxun Hao
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引用次数: 0
摘要
目的：攀登唑（CLB）是一种广谱咪唑类抗真菌药物，其主要问题是水溶性低。为了提高其水溶性和抗真菌活性，本研究合成了三种新的多组分晶体，并对其分子间相互作用进行了系统研究。这项工作有助于优化 CLB 产品配方，拓展其应用前景：本研究成功合成了CLB-丙二酸（CLB-MA）盐、CLB-丁二酸（CLB-SA）共晶体和CLB-己二酸（CLB-AA）共晶体三种新型多组分晶体。并通过单晶 X 射线衍射（SCXRD）、热重分析（TGA）、差示扫描量热法（DSC）、动态水蒸气吸附（DVS）和粉末溶解试验等方法对三种多组分晶体的晶体结构、热力学性质、溶解性、溶出性、吸湿性和抗真菌活性进行了全面表征。采用希尔斯菲尔德表面（HS）、分子表面静电位（MEP）、相互作用区域指示（IRI）和原子与分子（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防潮稳定性，其水溶性是纯 CLB 的 6-22 倍。同时，最低抑菌浓度（MIC）的测定证明，共晶体/盐的抗真菌活性强于攀唑。晶体结构的量子化学计算将多组分晶体中存在的相互作用可视化和量化，并探索了多组分晶体不同性能的微观机制。
Multi-component Crystal Strategy for Improving Water Solubility and Antifungal Activity of Climbazole.
Purpose: 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.
Methods: 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.
Results: 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.
期刊介绍：
Pharmaceutical Research, an official journal of the American Association of Pharmaceutical Scientists, is committed to publishing novel research that is mechanism-based, hypothesis-driven and addresses significant issues in drug discovery, development and regulation. Current areas of interest include, but are not limited to:
-(pre)formulation engineering and processing-
computational biopharmaceutics-
drug delivery and targeting-
molecular biopharmaceutics and drug disposition (including cellular and molecular pharmacology)-
pharmacokinetics, pharmacodynamics and pharmacogenetics.
Research may involve nonclinical and clinical studies, and utilize both in vitro and in vivo approaches. Studies on small drug molecules, pharmaceutical solid materials (including biomaterials, polymers and nanoparticles) biotechnology products (including genes, peptides, proteins and vaccines), and genetically engineered cells are welcome.
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