Liu Lixin, Zou Dongyu, Zhang Yunan, Zhang Qiang, Feng Yanru, Guo Yingxue, Liu Yingli, Zhang Xuesong, Cheng Guangdong, Wang Chaoxing, Zhang Yunjie, Zhang Lei, Wu Lili, Chang Liang, Su Xin, Duan Yu, Zhang Yanfei, Liu Moqi
College of Pharmacy, Jiamusi University, Jiamusi 154007, China.
College of Pharmacy, Jiamusi University, Jiamusi 154007, China.
Eur J Pharm Biopharm. 2020 Sep;154:62-73. doi: 10.1016/j.ejpb.2020.06.018. Epub 2020 Jul 6.
Base on improving the solubility and permeability of enoxacin (EX) to enhance the antibacterial activity in vitro, three new pharmaceutical salts/cocrystals of EX with oxalic acid (EX·0.5(CHO)·2(HO)), malonic acid ((HEX)·CHO) and fumaric acid ((HEX)·CHO) have been designed, synthesized and characterized. Comprehensive analysis structure and Hirshfeld surface reveal that the hydrogen bonds/CAHBs formed by the N atom in the piperazine ring from EX molecule with the carboxylic acid group in the coformer could form a stable crystal structure. It is universally acknowledged that improving the solubility of the EX (BCS class II) to make it a BCS class I drug would obtain a Bioequivalence of immunity to the drug trial. The solubilities of three pharmaceutical salts/cocrystals of EX with dicarboxylic acids are consistent with expectation that they are dramatically improved in pure water than pure enoxacin, and the solubility order of three pharmaceutical salts/cocrystals of EX is consistent with coformers solubility. The permeabilities of three pharmaceutical salts/cocrystals of EX are improved compared with the pure enoxacin, and the variation tendency is consistent with the solubilities of three pharmaceutical salts/cocrystals of EX. In addition, the antibacterial activities in vitro of three pharmaceutical salts/cocrystals of EX are improved compared with the corresponding parent compound (EX), which change the order is consistent with the solubility and permeability. Simultaneously, the hygroscopic stabilities of three pharmaceutical salts/cocrystals are surpassing pure EX, and the hygroscopic stability of molecular cocrystal EX-OXA is better than ionic cocrystal EX-MLO and EX-FUM. This implies that preparation of the pharmaceutical salts/cocrystals of EX with oxalic acid, malonic acid and fumaric acid could not only enhance the antibacterial activity of EX, which base on improving the solubility and permeability of EX, but also improve the hygroscopic stability of EX.
基于提高依诺沙星（EX）的溶解度和渗透性以增强其体外抗菌活性，设计、合成并表征了EX与草酸（EX·0.5(CHO)·2(HO)）、丙二酸（(HEX)·CHO）和富马酸（(HEX)·CHO）形成的三种新型药用盐/共晶体。综合结构分析和 Hirshfeld 表面显示，EX 分子哌嗪环中的 N 原子与共形成物中的羧酸基团形成的氢键/CAHBs 可形成稳定的晶体结构。众所周知，改善 EX（BCS Ⅱ类）的溶解度使其成为 BCS Ⅰ类药物可获得免于药物试验的生物等效性。EX 与二元羧酸形成的三种药用盐/共晶体在纯水中的溶解度比纯依诺沙星显著提高，符合预期，且三种药用盐/共晶体的溶解度顺序与共形成物的溶解度一致。与纯依诺沙星相比，EX 的三种药用盐/共晶体的渗透性得到改善，变化趋势与三种药用盐/共晶体的溶解度一致。此外，EX 的三种药用盐/共晶体的体外抗菌活性比相应的母体化合物（EX）有所提高，变化顺序与溶解度和渗透性一致。同时，三种药用盐/共晶体的吸湿稳定性优于纯 EX，分子共晶体 EX - OXA 的吸湿稳定性优于离子共晶体 EX - MLO 和 EX - FUM。这表明制备 EX 与草酸、丙二酸和富马酸的药用盐/共晶体不仅可以基于提高 EX 的溶解度和渗透性来增强 EX 的抗菌活性，还可以提高 EX 的吸湿稳定性。
