Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India.
Department of Pharmacy, School of Chemical Science and Pharmacy, Central University of Rajasthan, Bandar Sindri, Ajmer, Rajasthan 305 817, India.
Mol Pharm. 2020 Dec 7;17(12):4435-4442. doi: 10.1021/acs.molpharmaceut.0c00090. Epub 2020 Nov 16.
With the aim of developing multidrug solids through a tuned crystal engineering approach, we have selected two antiurinary infective drugs, namely, nitrofurantoin (NF) and trimethoprim (TMP) and isolated eight binary drug-drug solid solvates along with a nonsolvated cocrystal. Crystal structure analyses were performed for eight of these solids and rationalized in terms of known supramolecular synthons formed by pyrimidine, imide, and amine functionalities. Notably, the TMP-NF anhydrous cocrystal and its ionic cocrystal hydrate exhibit enhanced equilibrium solubilities compared to pure NF or the simple NF hydrate. Furthermore, the ionic cocrystal hydrate exhibits greater antibacterial activity against the Gram-negative bacteria, , compared to the parent TMP and NF at the lowest concentration of 3.9 μg/mL. This study indicates initial pathways using the cocrystal methodology that would help to eventually arrive at an antiurinary cocrystal with optimal properties.
为了通过优化晶体工程方法开发多药物固体，我们选择了两种抗尿路感染药物，即呋喃妥因（NF）和甲氧苄啶（TMP），并分离出八种二元药物-药物固溶体以及一种非溶剂共晶。对其中的八种固体进行了晶体结构分析，并根据嘧啶、酰亚胺和胺官能团形成的已知超分子连接基进行了合理化。值得注意的是，TMP-NF 无水共晶及其离子共晶水合物与纯 NF 或简单的 NF 水合物相比，具有更高的平衡溶解度。此外，离子共晶水合物对革兰氏阴性菌 的抗菌活性比母体 TMP 和 NF 更强，在最低浓度 3.9 μg/mL 时就是如此。本研究表明，使用共晶方法的初步途径将有助于最终获得具有最佳性能的抗尿路感染共晶。
