Improving the solubility, hygroscopicity and permeability of enrofloxacin by forming 1:2 pharmaceutical salt cocrystal with neutral and anionic co-existing p-nitrobenzoic acid

With the purpose of improving the solubility and reducing the hygroscopicity of enrofloxacin (ENR), an unreported pharmaceutical salt cocrystal of enrofloxacin with both neutral and anionic p-nitrobenzoic acid (PNB) (ENR-PNB, C19H23FN3O3 center dot C7H4NO4 center dot C7H5NO4) was designed and synthesized by changing the reaction molar ratio (1:2) of ENR and coformer PNB on the basis of summarizing the past experience of our group, and its crystal structure was characterized. Single-crystal X-ray diffraction (SCXRD) analysis revealed that the salt cocrystal consists of ENR+, PNB- and PNB neutral molecule in a 1:1:1 ratio. The two asymmetric units that become centrosymmetric form an X-shaped structure centered on the ENR dimer R-2(2)(20). The adjacent X-shaped structures are interconnected by hydrogen bonds to form 1D chain and form the octamer R-8(8)(42) at the same time. As we expected, the formation of the salt cocrystal ENR-PNB results in a simultaneous improvement in the solubility and hygroscopicity of ENR. This may be the fact that ENR and PNB depend on CAHBs to raise the hydrous enthalpy of salt cocrystal. And the presence of PNB neutral molecules lower hygroscopicity of ENR in high humidity environments. Unexpectedly, the permeability of ENR-PNB was also increased compared to that of pure ENR. It is speculated that the number of polar sites in the system is greatly reduced because of hydrogen bonds formation, which increases the permeability of the ENR salt cocrystal. In addition, the in vitro antibacterial activities of ENR-PNB are enhanced at different concentrations compared to ENR. The present study implies that it is possible to improve the solubility, hygroscopic stability, permeability and antibacterial activity of enrofloxacin by changing the chemical reaction molar ratio to form salt cocrystal containing both neutral and anionic coformers, which provides a new strategy and insight to simultaneously improve the solubility and hygroscopicity and even permeability of the active ingredients of solid drugs.

Automated summary

This study designed and synthesized a pharmaceutical salt cocrystal of enrofloxacin with p-nitrobenzoic acid to improve its solubility and reduce its hygroscopicity. The salt cocrystal was characterized by its crystal structure and found to consist of enrofloxacin cations, p-nitrobenzoic acid anions, and p-nitrobenzoic acid neutral molecules in a 1:1:1 ratio. The presence of the salt cocrystal resulted in improved permeability and antibacterial activity of enrofloxacin.