Controls of Transformation Between Amorphous and Crystal Ceftiofur Free Acid

Ceftiofur is a third generation cephalosporin antibiotic, which has a wide spectrum of activity against Gram-positive and Gram-negative bacteria including β-lactamase-producing strains. It can be used as veternary medicine as the sodium salt, the hydrochloride, and the free acid. Among them, the free acid was found to be the best for clinical therapy. Ceftiofur free acid could  exist in either amorphous or crystalline state. Generally, amorphous ceftiofur free acid will be much easier to obtain in the separation or purification process of it .In this research, the crystallization process of ceftiofur was investigated in detail by using several PAT tools, such as ATR-FTIR, FBRM, PVM and Raman spectroscopy. The crystal morphology and the structure of the final product was also analyzed by traditional off line tools such as XRD, DSC and SNMR. The effect of operating parameter, such as solvent, temperature, dosing rate and agitation speed, on the solid state of the final product was evaluated. Optimum conditions for manufacturing both forms were successfully developed. It was also found from experiments that the amorphous state ceftiofur can transform into crystalline state in appropriate conditions although it may take a very long period. The mechanism of this transformation was investigated using the in situ tools mentioned above.