Norfloxacin-NSAID Pharmaceutical Salts: Structure-Property Relationships for Enhanced Solubility and Stability

Area of Science:

• Pharmaceutical Chemistry
• Materials Science
• Drug Delivery

Background:

• Antibiotic dosing challenges include mucosal damage and resistance.
• Norfloxacin (NOR) exhibits poor oral bioavailability due to pH-dependent solubility.

Purpose of the Study:

• To develop novel drug-drug pharmaceutical salts of NOR.
• To enhance NOR's solubility, stability, and bioavailability.
• To investigate the impact of salt formation on NOR and NSAID performance.

Main Methods:

• Synthesis of NOR salts with ketoprofen (KET), dexketoprofen (DKT), and niflumic acid (NIF) via mechanochemical and slurry methods.
• Characterization using thermal, spectroscopic, and X-ray diffraction techniques.
• Computational analysis (DFT, QTAIM) of crystal structures and supramolecular interactions.

Main Results:

• Novel NOR-KET, NOR-DKT, and NOR-NIF salts were successfully synthesized and characterized.
• Salt crystal structures revealed tetrameric assemblies with distinct supramolecular stabilization (hydrogen bonds, π-π interactions).
• Salts demonstrated suppressed NOR hydration, improved stability at physiological pH, enhanced solubility (especially NOR-KET and NOR-DKT), and controlled dissolution profiles.

Conclusions:

• Pharmaceutical salt formation is an effective strategy to overcome NOR's solubility and stability limitations.
• The developed salts offer a promising framework for improving NOR and other challenging APIs.
• Supramolecular interactions within the salts significantly influence their pharmaceutical performance.