Study On The Anti-solvent Crystallization Process Of Sulbactam Sodium

Sulbactam sodium is one of the most commonly used beta-lactamase inhibitors.In this paper,the dissolution and crystallization process of sulbactam sodium was systematically studied to solve the problems with the current sulbactam sodium crystalline products.The solubility of sulbactam sodium in binary systems of ethanol-water and isopropanol-water was determined by static method with different temperature and solvent composition.Then the optimal solvent system and composition for the antisolvent crystallization of sulbactam sodium was determined.The fitting results of four solubility models on the measured solubility data were compared,and the most suitable solubility model for sulbactam sodium in two solvent systems was determined.The metastable behavior of sulbactam sodium in a binary mixed solvent was explored.The super-solubility of sulbactam sodium in different mixed solvent systems,different initial solution concentrations,different anti-solvent dropping rates,different stirring rates and different crystallization temperatures was determined by dynamic visual inspection.The crystallization metastable zone width of sulbactam sodium under different conditions was calculated.The effects of different crystallization conditions on the super-solubility and the metastable zone width were determined to obtain the suitable operating range for sulbactam sodium antisolvent crystallization.Based on the thermodynamics and metastable behavior of sulbactam sodium,the sulbactam sodium crystallization process was systematically studied.The effect of sulbactam penicillamine impurity on the particle size distribution of sulbactam sodium was determined.A sulbactam sodium antisolvent crystallization process was developed.Theorthogonal experiment_L27?7?₃1 3?8?was used to optimize the anti-solvent crystallization of sulbactam sodium.The effects of six factors and three interactions on crystal size distribution,purity and comprehensive scores of the two were considered,included aging time,volume of anti-solvent used,volume fraction of ethanol in the anti-solvent,rate of addition of the anti-solvent,stirring rate,crystallization temperature,and the interaction between the aging time and the volume of the anti-solvent,the interaction between the aging time and the volume fraction of ethanol in the decanting agent,the interaction between the volume of the anti-solvent used and the volume fraction of ethanol in the anti-solvent.At last,the optimal operation plan was obtained.Through this operation plan,sulbactam sodium with high quality can be prepared,whose purity was over 97%and crystal size distribution D[4,3]was about 290?m.