Sun Wei, Huo Ruili, Duan Jingzhong, Xiao Jixiang, Wang Yan, Zhou Xiaoping
School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China.
Pharmaceutics. 2024 Nov 26;16(12):1519. doi: 10.3390/pharmaceutics16121519.
: 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-HO (2CHFNO·CHO·2HO) and SPX-AZA-HO (4CHFNO·2CHO·5HO). : 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. : 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-HO has much higher antibacterial activity on and than SPX. : 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.
为提高司帕沙星（SPX）的溶解度和渗透性，并增强其体外抗菌活性，本文合成并表征了两种未见报道的药用结晶盐。一种是司帕沙星与庚二酸（PIA）的水合晶体，另一种是司帕沙星与壬二酸（AZA）的水合晶体，即SPX - PIA - H₂O（2C₁₉H₂₂FN₃O·C₇H₁₂O₄·2H₂O）和SPX - AZA - H₂O（4C₁₉H₂₂FN₃O·2C₉H₁₆O₄·5H₂O）。
采用单晶X射线衍射、粉末X射线衍射、差示扫描量热法、热重分析和红外光谱等固态表征方法分析了两种结晶盐的结构和纯度。此外，通过构建 Hirshfeld 表面并通过 Hirshfeld 表面分析绘制特定的实空间函数，研究了两种晶体盐分子之间的相互作用特性。使用包括最低抑菌浓度（MIC）测试在内的既定测定方法，评估了两种结晶盐在生理条件下的溶解度、跨模拟生物膜的扩散率以及对特定细菌菌株的体外抗菌活性。
单晶X射线衍射和 Hirshfeld 表面分析表明，SPX 与 PIA 通过电荷辅助氢键 N1 - H1e···O10（1.721 Å，173.24°）、N5 - H⁵a···O11（1.861 Å，169.38°）形成稳定的晶体结构，与 AZA 通过电荷辅助氢键 N5 - H⁵B···O8（1.810 Å，154.55°）、N4 - H⁴B···O6（1.806 Å，174.97°）形成稳定的晶体结构。两种结晶盐的结合位点位于 SPX 哌嗪环上的氮原子处。与 SPX 相比，两种结晶盐的平衡溶解度分别提高了1.17倍和0.33倍，两种结晶盐的渗透性分别提高了26.6%和121.9%。此外，SPX - AZA - H₂O 对[具体细菌1]和[具体细菌2]的抗菌活性比 SPX 高得多。
本研究成功合成了司帕沙星（SPX）的两种结晶盐，显著提高了其溶解度和扩散率，并增强了其对靶向细菌物种的抗菌效果。这些突破为抗菌药物开发领域的创新进展奠定了基础。
