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

Abstract

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.

Ciprofloxacin salts of benzene mono/di-carboxylate: crystal structures and the improvement of solubility

“…13 The relationship between the supramolecular structures and solubility was studied to find a way to improve the solubility of APIs. 10,14–19…”

First Cocrystallization of Gatifloxacin with Nutraceuticals Displays the Ameliorated In Vitro/Vivo Biopharmaceutical Property and Increased Antibacterial Activity

“…Although the solubility of GAT was increased to a certain level through salt formation, the permeability and in vivo pharmacokinetic properties have not been thoroughly investigated. 18 In addition, the selected saltforming reagent has little effect on the durability of GAT due to its limited pharmacological effects. Considering the defective circumstances of the current research on GAT solid preparations and acknowledging the advantages of counterions in modifying the lattice structure as well as improving the properties of the original drug, we strongly suggest selecting pharmacologically acceptable and ideal cocrystallization formers to achieve precise self-assembly of GAT.…”

“…In view of the ability to improve efficacy, eliminate drug resistance, and achieve synergistic treatment, drug salt formation strategies have received continuous attention from pharmaceutical researchers. , Additionally, studies have found that removing zwitterions in their structure through the salt formation strategy is one of the effective means to improve the physicochemical property and even bioavailability for fluoroquinolones. ,– Unfortunately, for all we know, merely one molecular salt of GAT with 2,3-dihydroxybenzoic acid has been reported so far. Although the solubility of GAT was increased to a certain level through salt formation, the permeability and in vivo pharmacokinetic properties have not been thoroughly investigated . In addition, the selected salt-forming reagent has little effect on the durability of GAT due to its limited pharmacological effects.…”