Improving Solubility and Avoiding Hygroscopicity of Gatifloxacin by Forming Pharmaceutical Salt of Gatifloxacin‐2,3‐Dihydroxybenzoic Acid Based on Charge‐Assisted Hydrogen Bonds

• Published in: Crystal research and technology (1979) 2022-06, Vol.57 (6), p.n/a
• Main Authors: Liu, Lixin, Liu, Moqi, Zhang, Yunan, Sun, Weitong, Li, Jinjing, Feng, Yanru, Geng, Yiding, Cheng, Guangdong, Gong, Yixia, Guo, Yingxue, Wu, Lili, Wang, Chaoxing, Liu, Yingli
• Format: Article
• Language: English
• Subjects: CAHBs; charge transfer; crystal structure; gatifloxacin; solubility
• ISSN: 0232-1300; 1521-4079
• DOI: 10.1002/crat.202100198

To improve the solubility of the fluoroquinolone drug gatifloxacin (GAT), a pharmaceutical salt of GAT with 2,3‐dihydroxybenzoic acid (2,3‐HBA) is designed, synthesized, and characterized. This work is based on previous research into the synthesis of the pharmaceutical salts/cocrystals of fluoroquinolones. A comprehensive assessment of the crystal structure and the molecular electrostatic potential, as well as a Hirshfeld surface analysis, revealed that the H protons of the carboxylic groups in 2,3‐HBA are transferred to the N of the GAT piperazine ring. This results in the ionization of GAT to form charge‐assisted hydrogen bonds (CAHBs) and the construction of a crystal structure. It is precisely the conversion of GAT from a neutral state to an ionic state that results in a significant increase in the solubility of GAT‐2,3‐HBA. Surprisingly, in the process of increasing its solubility, the hygroscopic stability and the antibacterial activities in vitro of GAT‐2,3‐HBA is also superior to GAT. In this study, a pharmaceutical salt of gatifloxacin with targeted structures and desired properties, based on CAHBs is successfully designed and synthesized. These encouraging results suggest that CAHBs play a crucial role in adjusting molecular packing through a co‐crystallization strategy, thus improving the physicochemical properties of fluoroquinolones. With the aim to improve the solubility of gatifloxacin (GAT), a single crystal of GAT with 2,3‐Dihydroxybenzoic acid (2,3‐HBA) GAT‐2,3‐HBA (C19H23FN3O4·C7H5O4) has been prepared based on theoretical analysis via molecular electrostatic potential. Surprisingly, in the process of increasing the solubility of GAT‐2,3‐HBA, the hygroscopic stability and antibacterial properties of GAT‐2,3‐HBA are also higher than GAT.