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The use of antibiotics is usually associated with mucosal damage and antimicrobial resistance due to inefficient dosing. This issue is particularly relevant for norfloxacin (NOR), whose amphoteric nature leads to strongly pH-dependent solubility and low oral bioavailability. To overcome these limitations, this work presents three novel drug–drug pharmaceutical salts of NOR with the anti-inflammatory drugs ketoprofen (KET), dexketoprofen (DKT), and niflumic acid (NIF). Salts were synthesized by mechanochemical and slurry strategies and fully characterized using thermal, spectroscopic, and X-ray diffraction techniques. The crystal structure, along with DFT and QTAIM computational analyses, showed that salts are governed by tetrameric assembly formation. However, while NOR–KET and NOR–DKT are stabilized by robust charge-assisted hydrogen bonds, NOR–NIF packing arrangement is dominated by weaker hydrogen bonds together with π–π and CF3···π interactions. These supramolecular differences were directly reflected in the pharmaceutical performance. The salts suppressed the rapid hydration of NOR under aqueous environments and showed improved stability at physiological pH. Moreover, NOR–KET and NOR–DKT significantly enhanced the solubility of both NOR and the corresponding NSAIDs in PBS at pH 6.8, while all salts provided a more controlled NOR dissolution profile under acidic conditions. These findings demonstrate that salt formation is an effective strategy to overcome the solubility and stability limitations in NOR and NSAIDs, offering a framework for improving the performance not only of NOR but also of other APIs facing similar challenges.