Salt Cocrystal and Salt of Marbofloxacin with Butenedioic Acid: Impact of <i>cis</i>–<i><i>trans</i></i> Isomerism of Coformer on the Conformation and Properties of Marbofloxacin

Abstract

Based on the study of the effect of positional isomerism of coformer functional groups on the cocrystallization and physicochemical properties of the active pharmaceutical ingredients, the impact of cis–trans isomeric butenedioic acid as coformers on the conformation, crystal structure, and its physicochemical properties of marbofloxacin was further explored. In this work, fumaric acid (FA) and maleic acid (MA) with different configurations were chosen as coformers to synthesize the pharmaceutical salt cocrystal (MBF-FA-H2FA) and salt (MBF-MA) of marbofloxacin (MBF), and their structures were fully characterized. Significant differences between the conformations of marbofloxacin in the salt cocrystal and in salt were found. In the salt cocrystal, the N atom of the piperazine group from marbofloxacin is coplanar with the pyridone ring, and the whole is straight like fumaric acid, whereas the marbofloxacin piperazine group in the salt is bent like the maleic acid configuration. Furthermore, the conformational variability of marbofloxacin in the salt cocrystal and the salt resulted in different crystal structures and opposite physicochemical properties. Notably, both multicomponent crystals have a surface hydrophilic intercalation structure. However, the salt cocrystal and salt exhibited different solubility and permeability. Specifically, the MBF-MA salt showed improved solubility and permeability, while the MBF-FA-H2FA salt cocrystal showed a decreased solubility and permeation rate compared to MBF. In addition, in vitro bacterial inhibitory activity assays indicated that the MBF-MA salt has stronger inhibitory activity against Gram-negative and Gram-positive bacterial strains than the MBF-FA-H2FA salt cocrystal and pure MBF