Norfloxacin (NOR), a broad-spectrum fluoroquinolone antibiotic, is widely used to treat bacterial infections. However, its clinical application is hindered by poor aqueous solubility and low oral bioavailability. To address these limitations, this study developed two novel pharmaceutical salts of NOR using 4-fluorobenzoic acid (4-FA) and 2-fluorobenzoic acid (2-FA) as counterions. The salts were synthesized via slow evaporation crystallization, and their structures were characterized by single-crystal X-ray diffraction (SCXRD). Comprehensive solid-state analyses, including powder X-ray diffraction (PXRD), Fourier-transform infrared (FT-IR) spectroscopy, and differential scanning calorimetry (DSC), confirmed the successful formation of the salts. Notably, the salt formation significantly improved NOR’s solubility and dissolution behavior. Furthermore, these modifications enhanced NOR’s antibacterial efficacy, as evidenced by stronger bacterial inhibition and reduced minimum inhibitory concentration (MIC) values. This study demonstrates a promising strategy for optimizing the biopharmaceutical performance of NOR through salt formation.
Cite this paper
Wang, S. , He, J. , Ruan, C. , Cao, P. , Zhang, Z. and Jiang, C. (2026). Enhancing Norfloxacin’s Solubility and Antibacterial Activity through Pharmaceutical Salt Formation with Fluorobenzoic Acids. Open Access Library Journal, 13, e14832. doi: http://dx.doi.org/10.4236/oalib.1114832.
He, Y., Orton, E. and Yang, D. (2018) The Selection of a Pharmaceutical Salt—The Effect of the Acidity of the Counterion on Its Solubility and Potential Biopharmaceutical Performance. Journal of Pharmaceutical Sciences, 107, 419-425. https://doi.org/10.1016/j.xphs.2017.10.032
Li, X. and Jiang, C. (2025) The Crystal Structure of 4-(3-Carboxy-1-Ethyl-6-Fluoro-4-Oxo-1,4-Dihydroquinolin-7-Yl)Piperazin-1-Ium 4-Hydroxy-3,5-Dimethoxybenzoate Monohydrate, C25H30FN3O9. Zeitschrift für Kristallographie—New Crystal Structures, 240, 509-510. https://doi.org/10.1515/ncrs-2025-0090
Sun, Y., Gu, Z. and Jiang, C. (2024) The Crystal Structure of 4-(3-Carboxy-1-Ethyl-6-Fluoro-4-Oxo-1,4-Dihydroquinolin-7-yl)Piperazin-1-Ium 2-Carboxy-6-Nitrobenzoate Monohydrate, C24H25FN4O10. Zeitschrift für Kristallographie—New Crystal Structures, 239, 865-867. https://doi.org/10.1515/ncrs-2024-0203
Lin, S., Lou, C. and Jiang, C. (2023) The Crystal Structure of 4-(3-Carboxy-1-Cyclopropyl-6-Fluoro-8-Methoxy-4-Oxo-1,4-Dihydroquinolin-7-Yl)-2-Methylpiperazin- 1-Ium 2,5-Dihydroxybenzoate Methanol Solvate, C27H32FN3O9. Zeitschrift für Kristal-lographie—New Crystal Structures, 238, 841-843. https://doi.org/10.1515/ncrs-2023-0228
Xu, Y., Jiang, L. and Mei, X. (2014) Supramolecular Structures and Physicochemical Properties of Norfloxacin Salts. Acta Crystallographica Section B Structural Science, Crystal Engineering and Materials, 70, 750-760. https://doi.org/10.1107/s2052520614011718
Basavoju, S., Boström, D. and Velaga, S.P. (2012) Pharmaceutical Salts of Fluoroquinolone Antibacterial Drugs with Acesulfame Sweetener. Molecular Crystals and Liquid Crystals, 562, 254-264. https://doi.org/10.1080/10426507.2012.669673
Gopi, S.P., Ganguly, S. and De-siraju, G.R. (2016) A Drug-Drug Salt Hydrate of Norfloxacin and Sulfathiazole: Enhancement of in Vitro Biological Properties via Improved Physicochemical Properties. Molecular Pharmaceutics, 13, 3590-3594. https://doi.org/10.1021/acs.molpharmaceut.6b00320
Bhattacharya, B., Mondal, A., Soni, S.R., Das, S., Bhunia, S., Bal Raju, K., et al. (2018) Multidrug Salt Forms of Norfloxacin with Non-Steroidal Anti-Inflammatory Drugs: Solubili-ty and Membrane Permeability Studies. CrystEngComm, 20, 6420-6429. https://doi.org/10.1039/c8ce00900g
Chierentin, L. and Salgado, H.R.N. (2015) Review of Properties and Analytical Methods for the Determination of Norfloxacin. Critical Reviews in Analytical Chemistry, 46, 22-39. https://doi.org/10.1080/10408347.2014.941456
Liang, D., Li, F., Duan, J., Sun, W. and Yu, X. (2024) Two Novel Hydrate Salts of Norfloxacin with Phe-nolic Acids and Their Physicochemical Properties. Antibiotics, 13, Article 888. https://doi.org/10.3390/antibiotics13090888
Gunnam, A. and Nangia, A.K. (2023) Novel Hydrate and Anhydrate Cocrystals/Salts of Norfloxacin and Their Physicochemical Properties. Crystal Growth & Design, 23, 4198-4213. https://doi.org/10.1021/acs.cgd.3c00023
Qiu, S., Deng, X., Qian, K., Yang, J. and Ma, Y. (2024) Study on the Structure, Solubilities, Antibacterial Ac-tivities and in Vivo Toxicity of Hesperetin and Norfloxacin Cocrystal. Pharma-ceutical Chemistry Journal, 58, 765-774. https://doi.org/10.1007/s11094-024-03205-y