Study On Reactive Crystallization Process Of AE-active Ester

AE active ester is an important intermediate of semisynthetic cephalosporins.Due to the continuous development of cephalosporin antibiotics,the production of AE active ester in China is also rising rapidly.However,there are still some problems in the production process,such as unstable product quality,low crystallization yield and uneven crystal size distribution.In this paper,the reactive crystallization process of AE active ester was systematically studied,including process optimization of AE active ester reactive crystallization process,on-line monitoring of AE active ester reactive crystallization process by process analysis technology,continuous preparation of AE active ester,and fitting of particle size distribution model of AE active ester.The effects of the reaction conditions,such as the crystal size distribution of the product,the reaction rate,the crystallization rate and the reaction conditions were investigated.The results showed that the optimum rotational speed of AE active ester was 250 The results show that: rpm;medium speed drip condensation agent(dropping time is about 1.5h)has more advantages in purity and yield;the problem of sudden increase in the number of small particles in the process of condensation agent dropping can be solved by adding seed crystal,and large particle size AE active ester products can be obtained;through process optimization,the purity of AE active ester products obtained by repeated experiments under the optimal process is more than or equal to 99.5% The yield was more than 89.5%.Combined with the optimization results of batch reaction process,the continuous crystallization process of AE active ester was studied.By investigating the conditions of raw material feeding mode,stirring speed and raw material feeding ratio,a continuous preparation method of AE active ester was obtained.The purity and yield of AE active ester prepared by this method are qualified and the particle size distribution is uniform.The purity is above 99.5%,and the final yield is more than 91.0%.According to AE active ester samples provided by Shandong Debang Pharmaceutical Co.,Ltd.,the mathematical model of particle size distribution was studied,and the goodness of fit(R2,AIC and RMSE)was evaluated.The results show that lognormal,gamma and Weibull function models can be used to fit and predict the particle size distribution model of AE active ester.The R2 of the model is above 0.99,and the AIC and RMSE values obtained by fitting are small.By comparing the calculated values of mean diameter,median diameter and variance of the three models,as well as the experimental values of mean diameter,median diameter and variance,it can be concluded that the difference between the predicted value of gamma and the experimental value is the smallest,which is consistent with the evaluation result of goodness of fit.The fitting results of sample size distribution show that the pharmaceutical intermediate particles produced by the factory can be quantitatively characterized by a specific continuous function model.The regression coefficient,goodness of fit and PSD parameters were used to quantitatively and sensitively describe the particle size distribution characteristics.The fitting model of particle size distribution is of great significance to the quality control of products and the optimization and adjustment of process parameters.