A Portfolio of Ciprofloxacin Hydrochloride Ionic Cocrystals with Phenolic Acids for Tailoring Dissolution and Solubility

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Ciprofloxacin is a potent antibiotic used for the treatment of bacterial infections located mainly in the urinary and pulmonary tracts. In this work, we report the formation of ionic cocrystals of ciprofloxacin hydrochloride (CiHCl) in combination with phenolic acid derivatives like 2,3-dihydroxybenzoic acid (23DBA), 2,4-dihydroxybenzoic acid (24DBA), 2,5-dihydroxybenzoic acid (25DBA), 3,4-dihydroxybenzoic acid (34DBA), 3,5-dihydroxybenzoic acid (35DBA), and gallic acid (GAL). This series of phenolic acids was selected to systematically explore the impact on the biopharmaceutical properties of CiHCl originating from the formation of ionic cocrystals with species containing phenolic groups in different numbers and symmetry. The solids were obtained by solution-based crystallization (viz., slurry, reaction crystallization, solvent evaporation) and mechanochemical methods (LAG), and they were fully characterized by PXRD, TG, DSC, IR, NMR, and elemental analysis. Single-crystal X-ray diffraction studies were performed for anhydrous CiHCl and CiHCl·23DBA. Structural comparison by Hirshfeld surface and fingerprint analysis of the anhydrous and hydrated forms (CiHCl and CiHCl·H2O) with the ionic cocrystals (CiHCl·4HBA, CiHCl·23DBA, and CiHCl·35DBA·H2O) revealed that changes in the hydrogen bonding and π–π interactions play a fundamental role in the supramolecular organization in the solid state and the successful establishment of cocrystals. In the anhydrous salt, the chloride ion coordination environment is determined by two [N–H]+···Cl– and C–H···Cl– hydrogen bonds. In CiHCl·H2O, CiHCl·4HBA, CiHCl·23DBA, and CiHCl·35DBA·H2O, these interactions are partially or entirely replaced by [N–H]+···O, O–H···Cl– and O–H···O hydrogen bonds with water and coformer molecules, respectively, mostly at the expense of C–H···Cl– interactions. The presence of two available hydrogen bonding donors in the phenolic acids is essential in the formation of cocrystals, and therefore, coformers compromised in intramolecular O–H···O hydrogen bonds, such as 2HBA and 26DBA, were not successful. In most cases, dissolution rates and solubilities of the cocrystals were lower than for CiHCl·H2O, covering overall a range of an order of magnitude. The trend found for these parameters correlates with the solubility of the coformers. The cocrystal with the most soluble coformer (35DBA) showed phase transformation, the highest dissolution rate constant, and its solubilization surpasses that of the reference salt (CiHCl·H2O), demonstrating the utility of cocrystallization for generating a portfolio of ionic cocrystals with tailored properties.