A Twist in Cocrystals of Salts: Changes in Packing and Chloride Coordination Lead to Opposite Trends in the Biopharmaceutical Performance of Fluoroquinolone Hydrochloride Cocrystals

Fluoroquinolones are extensively used antibiotics that are generally prescribed as hydrochloride salts because the neutral forms display low solubility due to their zwitterionic character. Starting from the hydrochloride salts of ciprofloxacin (CiHCl) or (S,S)-moxifloxacin (MoHCl) and 4-hydroxybenzoic acid (4HBA) as a cocrystal former, two cocrystalline solids, CiHCl–4HBA and MoHCl–4HBA, were obtained in a salt/coformer stoichiometric ratio of 1:1. The cocrystalline phases were identified by X-ray powder diffraction analysis and further characterized by IR spectroscopy, thermogravimetric analysis-differential scanning calorimetry, and single crystal X-ray diffraction analysis. The novel solid phases could be formed using different methodologies, namely, solution-mediated phase transformation, solvent drop grinding, crystallization by solvent evaporation, and reaction crystallization. Pharmaceutically relevant properties such as phase stability, thermodynamic solubility, and dissolution rate were examined. All cocrystalline phases remained stable when suspended in acidic aqueous solutions and did not transform upon accelerated temperature/relative humidity exposition for 30 days. Interestingly, opposite trends in the thermal stability, solubility, and dissolution rate of the cocrystals were exhibited by the different fluoroquinolones in comparison to the parent starting salts. Upon heating, the CiHCl–4HBA cocrystal releases first the coformer before decomposing and displayed a lower solubility and dissolution rate in comparison to CiHCl·1.34H₂O. By contrast, the MoHCl–4HBA cocrystal melts in a single-phase transition process and showed enhanced solubility and dissolution rate when compared to the parent moxifloxacin salt. The similar composition of the cocrystals and the structural resemblance of the fluoroquinolones examined herein allowed for a detailed vis-à-vis comparison between the supramolecular structures in the solid-state and the physicochemical properties. The incorporation of 4HBA in the crystal lattice caused changes in the number, type, and strength of the intermolecular interactions between the ionic components (chloride and fluoroquinolinium cations), which could be related to the solubility and dissolution rate properties. While the cocrystal CiHCl–4HBA retained essential features of the supramolecular assembly found also for the starting hydrochloride and gave an overall three-dimensional hydrogen bonded network with the cocrystal former, MoHCl–4HBA showed a singular two-dimensional assembly, with linear chains formed between the 4HBA molecules and chloride ions through O–H···Cl^–···H–O hydrogen bonds in place of the usual charged-assisted N⁺–H···Cl^– interactions.