Synthesis and Characterization of Two Sparfloxacin Crystalline Salts: Enhancing Solubility and In Vitro Antibacterial Activity of Sparfloxacin

Abstract

Background: To improve the solubility and permeability of Sparfloxacin (SPX) and enhance its antimicrobial activity in vitro, two unreported pharmaceutical crystalline salts were synthesized and characterized in this paper. One is a hydrated crystal of Sparfloxacin with Pimelic acid (PIA), another is a hydrated crystal of Sparfloxacin with Azelaic acid (AZA), namely, SPX-PIA-H2O (2C19H23F2N4O3·C7H10O4·2H2O) and SPX-AZA-H2O (4C19H23F2N4O3·2C9H14O4·5H2O). Methods: The structure and purity of two crystalline salts were analyzed using solid-state characterization methods such as single-crystal X-ray diffraction, powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, and infrared spectroscopy. Additionally, the interaction characteristics between two crystal salt molecules were examined by constructing Hirshfeld surfaces and mapping specific real-space functions through Hirshfeld surface analysis. The solubility under physiological conditions, diffusivity across simulated biological membranes, and in vitro antibacterial activity against specific bacterial strains of two crystalline salts were evaluated using established assays, including minimum inhibitory concentration (MIC) tests. Results: Single-crystal X-ray diffraction and Hirshfeld surface analysis indicate that SPX forms stable crystal structures with PIA through charge-assisted hydrogen bonds N1-H1e···O10 (1.721 Å, 173.24°), N5-H5a···O11 (1.861 Å, 169.38°), and with AZA through charge-assisted hydrogen bonds N5-H5B···O8 (1.810 Å, 154.55°), N4-H4B···O6 (1.806 Å, 174.97°). The binding sites of two crystalline salts were at the nitrogen atoms on the piperazine ring of SPX. Compared with SPX, the equilibrium solubility of the two crystalline salts was improved by 1.17 and 0.33 times, respectively, and the permeability of the two crystalline salts was increased by 26.6% and 121.9%, respectively. In addition, SPX-AZA-H2O has much higher antibacterial activity on Pseudomonas aeruginosa and Bacillus subtilis than SPX. Conclusions: This research yielded the successful synthesis of two crystalline salts of Sparfloxacin (SPX), significantly improving its solubility and diffusivity, and bolstering its antibacterial efficacy against targeted bacterial species. These breakthroughs set the stage for innovative advancements in the realm of antimicrobial drug development.