Unveiling the Facilitation and Stabilization mechanisms of Oxygen-Rich coformers on cefmetazole sodium crystals

Cefmetazole sodium (CMZS), which is a semisynthetic cephamycin derivative, has been developed for more than forty years. However, only its amorphous form is obtained and it is quite difficult to obtain its crystalline form. Herein, ethylene glycol (EG) and polyethylene glycol (PEG) were found to be effective coformers of CMZS for forming solvate crystals through hundreds of crystallization experiments. The crystal structures of the CMZS solvates were determined by single-crystal X-ray diffraction, and it was found that all these coformers participated in the coordination with sodium ions and a complex hydrogen bond network was established within the crystal structures. Furthermore, stability experiment results indicated that the CMZS-PEG crystals demonstrated superior humidity stability and high-temperature resistance in comparison to the amorphous. Finally, the crystallization mechanism was investigated and the results of conformational analysis, energy computations, as well as porosity and molecular volume assessments indicated that the highly flexible molecular conformation of CMZS and the coordination effect of sodium ions may be the primary reasons for its difficulty in crystallization. Accordingly, EG and PEG which possess high coordination efficiency, suitable molecular dimensions, and exceptional adaptability to various CMZS packing configurations, effectively facilitate the successful formation of crystalline CMZS solvates.