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.
