Improving aqueous solubility of ciprofloxacin: three different stoichiometric hydrated salt forms with oxalic acid

Abstract

Ciprofloxacin (CIF) is a powerful synthetic antibiotic usually used for chest, skin, and bone infections when the patients have resisted other antibiotics. However, ciprofloxacin has a weakness in terms of solubility, especially in water between pH 6 and 8. Therefore, we propose the formation of novel salt forms of ciprofloxacin with oxalic acid (OXA) in order to alter and improve the solubility. Liquid assisted grinding (LAG) was used as a pre-screen for salt or co-crystal formation with nine candidates for the co-former based on known synthons. The solid-state characterization results confirmed that from these nine candidates, CIF is able to form hydrated salts only with oxalic acid (OXA). Interestingly, CIF-OXA forms hydrated salts with three different stoichiometric forms with different ratios between CIF and OXA. The appearance of hydrated salts with different stoichiometry is caused by the diversity of protonated/deprotonated forms in the OXA molecule, including OXA, OXA⁻, and OXA²⁻.The precise molecular structures of the products were confirmed by SC-XRD, which found that the three products are CIF₆⁺OXA₃²⁻·2H₂O (form A), CIF₂⁺OXA₁OXA₁²⁻·2H₂O (form B), and CIF₂⁺OXA₁OXA₂⁻·2H₂O (form C). Furthermore, all product forms reveal enhanced solubility in deionized water approximately 38.5, 66.0, and 41.0 times for form A, B, and C with respect to pure CIF.