Ciprofloxacin salts of benzene mono/di-carboxylate: crystal structures and the improvement of solubility

Abstract

To improve the solubility, a series of novel pharmaceutical salts prepared by ciprofloxacin as the active pharmaceutical ingredient (API) and phthalic acid and its isomers or substituted benzene carboxylic acids as the coformers were synthesized and structurally characterized. The solubility of these pharmaceutical salts is enhanced compared to the parent APIs. The solubility values of three benzene dicarboxylates of ciprofloxacin in phosphate buffer (pH = 6.8) are 20.5 times, 21.8 times, and 2.0 times that of ciprofloxacin, respectively. In particular, the solubility of ciprofloxacin salicylate hydrate has been dramatically improved (up to 349 times) in both neutral (1.45 and 1.32 mg mL⁻¹ at pH 6.4 and 6.8, respectively) and acidic (13.96 mg mL⁻¹ at pH 1.2) environments. Computational chemistry was employed to analyze the solubility of ciprofloxacin salts and elucidate the mechanisms underlying their enhanced solubility.