Study On Continuous Crystallization Process Of Cefradine

Cefradine is the first generation of semi-synthetic cephalosporin,which has strong resistance to bacteria and is widely used in the treatment of Gram-positive and Gram-negative bacteria.At present,cefradine separation and purification mainly adopt batch crystallization process,which has disadvantages such as high investment,high cost of equipment maintenance,difficult to control and quality differences between batches.Under the background of promoting the continuous crystallization process of Chinese government,two new technologies were designed and developed which can be applied to the continuous crystallization of cefradine.The solubility of cefradine in pure water with temperature and p H value in ethanol-water were measured by laser dynamic system experiment,which founded the data and theoretical foundation for the optimization of cefradine continuous crystallization kinetics and continuous crystallization process.According to the relevant empirical equations,four model equations were selected: Apelblat equation,λh equation,CNIBS/R-K equation and J-A equation to fit the solubility data,among which Apelblat equation and J-A equation had better fitting effect.The continuous crystallization kinetics of cefradine in the Mixed Suspension Mixed Product Removal(MSMPR)crystallizer and in the kettle-tube crystallizer were studied respectively.The nucleation kinetics equation and growth kinetics equation were obtained by fitting the data of continuous crystallization kinetics according to the grain size independent growth rate model.Temperature,stirring rate,suspension density and supersaturation all have effects on the kinetics of continuous crystallization process,and supersaturation has significant effects on the nucleation rate and growth rate of continuous crystallization process.The effects of operating parameters on the yield and particle size distribution of cefradine were studied and optimized by single factor experiment.At the crystallization temperature of 293.15 K,stirring rate of 180 r/min,p H=2.85,seed dosage of 3%(mass fraction),concentration of cefradine liquid of 11%(mass fraction),and retention time of33.3 min,continuous crystalline products with average particle size of 85.3 μm and yield of 76.62% were obtained.A new continuous crystallization process in kettle-tube crystallizer was studied systematically.The effects of different process parameters on the yield and particle size distribution of continuous crystallization products were studied by single factor experiment.At the conditions of stirring rate of 150 r/min,residence time of 50 min,feed liquid concentration of 9%,crystallization p H of 4.7-4.9 and crystallization temperature of288.15 K,continuous crystallized products with average particle size of 94 μm and yield of 73.85% were obtained.Compared with the MSMPR continuous crystallization process,the kettle-tube continuous crystallization process was more suitable for cefradine continuous crystallization.