Preparation and Physiochemical Analysis of Novel Ciprofloxacin / Dicarboxylic Acid Salts

Abstract

The crystal structures of four novel dicarboxylic acid salts of ciprofloxacin (CFX) with modified physicochemical properties, prepared by mechanochemical synthesis and solvent crystallization, are reported. A series of dicarboxylic acids of increasing molecular weight was chosen, predicted to interact via a carboxylic acid:secondary amine synthon. These were succinic (SA), glutaric (GA), adipic (AA) and pimelic (PA) acids (4, 5, 6, 7 carbon atoms respectively). Characterized by single crystal and powder X-ray diffraction, Fourier-Transform Infrared Spectroscopy, thermogravimetric analysis, differential scanning calorimetry, scanning electron microscopy and aqueous solubility measurements, these salts showed distinct physicochemical properties relative to ciprofloxacin base. Searches of the Cambridge Structural Database (CSD) confirmed CFX-SA, CFX-GA, CFX-AA and CFX-PA to be novel crystal structures. Furthermore, the GA salt has substantially higher solubility than the widely available hydrochloride monohydrate salt (CFX-HCl·H2O). CFX-SA, CFX-GA and CFX-AA showed minimum inhibitory concentration (MIC) of 0.008 g/L and CFX-PA showed MIC of 0.004 g/L. The prepared CFX salts retained antibacterial activity exhibiting equivalent antimicrobial activity to CFX-HCl·H2O. These salts have positive implications for increasing the application of CFX beyond conventional oral formulations and highlight mechanochemical activation as suitable production method.