Influence of Solvent Proton-Donating Ability on Polymorph Type and Crystal Morphology of Pharmaceuticals: Formation Mechanism of Enrofloxacin-Aspirin Cocrystal and Enrofloxacin-Salicylic Acid Salt Single Crystals

For the first time, the effect of the solvent system on the type and morphology of crystals during crystal preparation has been elucidated. • Investigated the principle of solvent proton-donating ability on the formation of salicylic acid from ASP hydrolysis and ENR-SA drug salts. • By regulating the solvent system, not only was the directed preparation of drug cocrystals/salts achieved, but the physicochemical properties of the drugs were also improved. During the synthesis of the ENR-ASP drug-drug cocrystal, we unexpectedly obtained not only single crystals of the ENR-ASP cocrystal but also single crystals of the ENR-salicylic acid (SA, a hydrolysate of ASP) pharmaceutical salt. These synthesis conditions were screened, and the resulting structures were characterized by SXRD, PXRD, and HOMO-LUMO calculations. The results showed that when an ethyl acetate-acetonitrile mixture was used as the solvent, ENR and ASP formed a cocrystal via hydrogen bonding. In contrast, when a methanol-acetonitrile mixture was used, ASP underwent hydrolysis to SA, and ENR and SA formed a salt via CAHB. Accordingly, MeOH, which has a strong proton-donating capacity, promoted the hydrolysis of ASP to SA and facilitated proton transfer between ENR and SA, leading to the formation of the ENR-SA pharmaceutical salt. In contrast, EtOAc, with a weak proton-donating capacity, neither induced hydrolysis of ASP nor enabled proton transfer between ENR and ASP, resulting in the formation of the ENR-ASP cocrystal. As expected, both crystalline forms exhibited higher solubility and permeability than the parent drugs. The cocrystal’s enhanced solubility may result from reduced lattice energy due to hydrogen bonding, whereas the salt’s improvement likely arises from CAHB via proton transfer. The observed changes in permeability may be due to altered local polarity caused by variations in polar sites within the crystal structures, which may also create favorable conditions for antibacterial activity. Furthermore, both forms showed superior anti-inflammatory activity to ASP, and their in vitro antibacterial activity exceeded that of ENR. Download: Download high-res image (241KB) Download: Download full-size image