Exploring the differences in crystal structure landscapes and physicochemical properties of enrofloxacin through the number of -OH in coformers: a case study

In the present work, the effect of the number of hydroxyl groups in the hydroxybenzoic acid on the cocrystallization of enrofloxacin, including the conformation of enrofloxacin in the crystals, packing and physicochemical properties, has been investigated in an attempt to explore the possible general relationship between the number of coformers hydroxyl groups and the changes in the properties of the active pharmaceutical molecule. With this purpose, two new enrofloxacin pharmaceutical salt crystals, enrofloxacin 3-hydroxybenzoic acid hydrate (ENR-3HBA-HYD) and enrofloxacin 3, 5 dihydroxybenzoic acid hydrate (ENR-3, 5HBA-HYD) have been synthesised and their crystal structures have been determined by infrared spectroscopy, differential scanning calorimetry, powder X-ray diffraction, and single-crystal X-ray diffraction. The conformational differences between the enrofloxacin molecules in the two hydrated salts were found to be very small and both have the same packing mode. Interestingly, the presence of one water molecule in the ENR-3HBA-HYD lattice stabilizes chain formation. Whereas the ENR-3, 5HBA-HYD lattice contains two water molecules that act as bridges between chains to build a 2D layered structure. The hydrogen bonding interactions of the two salts were further investigated with frontier molecular orbitals and molecular surface electrostatic potential. Additionally, Solubility and hygroscopicity experiments showed that ENR-3HBA-HYD has higher solubility and, conversely, ENR-3, 5HBA-HYD is more advantageous in anti-hygroscopicity. These differences in properties can be well explained by thermal analysis, Hirshfeld surface and energy framework analysis.