Levofloxacin–Niflumate Salt Development as a Strategy for Improving Physicochemical Properties and Modulating Antibiotic Potency and Anti-Inflammatory Performance

Ilma Nugrahani,1 Hidehiro Uekusa,2 Takaaki Hori,2 Yutong Wu,2 Marlia Singgih Wibowo,1 Afrillia Nuryanti Garmana,3 Febrina Ester Panjaitan1 1Department of Pharmacochemistry, School of Pharmacy, Bandung Institute of Technology, Bandung, West Java, 40132, Indonesia; 2Department of Chemistry, School of Science, Institute of Science Tokyo, Tokyo, 152-8551, Japan; 3Department of Pharmacology, School of Pharmacy, Bandung Institute of Technology, Bandung, West Java, 40132, IndonesiaCorrespondence: Ilma Nugrahani, School of Pharmacy, Bandung Institute of Technology, Bandung, West Java, 40132, Indonesia, Email [email protected]: This research aimed to develop and characterize a novel levofloxacin–niflumic acid salt, to improve its physicochemical properties, antibiotic potency, and anti-inflammatory effects.Methods: A 1:1 molar ratio salt was synthesized and its crystal structure determined using single-crystal X-ray diffractometry (SCXRD) also characterized using powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR). Scalability was evaluated via neat grinding, solvent-dropped grinding, hot melt mixing, and slurry techniques. Stability under controlled conditions (70– 80%RH/25– 30°C) was assessed using PXRD, DSC, and HPLC solubility measurements, levofloxacin’s antibiotic potency (microdilution), and niflumic acid’s anti-inflammatory activity (in vivo in Wistar rats) were also evaluated.Results: SCXRD confirmed the formation of a stable multicomponent salt, levofloxacin–niflumate. The slurry method successfully yielded a homogeneous powder with identical structural characteristics to the single crystal. Notably, the salt demonstrated enhanced physical and chemical stability compared to the individual drugs and their physical mixture. The solubility of niflumic acid was significantly increased, and the salt formation positively influenced both levofloxacin’s antibiotic potency and niflumic acid’s anti-inflammatory activity.Conclusion: The successful development of the levofloxacin–niflumate salt offers a promising strategy to improve the stability and potency of levofloxacin, along with enhanced niflumic acid solubility that contributes to improved anti-inflammatory action. This enhanced profile suggests the potential for more effective and efficient therapeutic use, which could improve patient compliance given the frequent co-prescription of these drugs. Keywords: levofloxacin, niflumic acid, multicomponent salt, stability, antimicrobial potency, anti-inflammatory activity