Inspiration for revival of old drugs: improving solubility and avoiding hygroscopicity of pipemidic acid by forming two pharmaceutical salts based on charge-assisted hydrogen bond recognitions

Abstract

In order to improve the solubility of pipemidic acid (PPA) which belongs to quinolones and becomes an “old drug” due to its low aqueous solubility that restricts its application, two unreported pharmaceutical salts of PPA with catecholcarboxylic acid (CCA) (HPPA·C₇H₅O₄·2(H₂O)) and m-hydroxybenzoic acid (MHA) (HPPA·C₇H₅O₃·C₇H₆O₃·2(H₂O)) have been designed, synthesized and characterized. A comprehensive analysis of the structure and Hirshfeld surface reveals that the CAHBs formed from the N atoms in the piperazine ring from PPA molecules with the carboxylic acid group in the coformers could have a stable crystal structure. As expected, the solubility experiments showed that the solubilities of the PPA–CCA and PPA–MHA were significantly improved compared with that of the PPA, which may be due to the increased hydration enthalpy resulting from the formation of CAHBs between PPA and coformers, which leads to increased solubility. Moreover, the antibacterial activities of PPA–CCA and PPA–MHA are also improved. At the same time, surprisingly, the permeability of PPA–CCA and PPA–MHA was also better than that of PPA. In addition, the hygroscopic stabilities of PPA–CCA and PPA–MHA were significantly improved compared with that of PPA. The reason may be due to that the hydrogen bonds between PPA and CCA weaken their attraction to external water molecules. Thus, the present work implies that CAHBs play a key role in adjusting the molecular packing via a cocrystallization strategy to improve the physicochemical properties of quinolones, which could offer a tremendous opportunity to recycle these “old” drugs and give them a new life.