Study On Continuous Crystallization Process Of Cefminox Sodium

Cefminox sodium is a cephalosporin antibiotic with dual bactericidal mechanism,which is mainly used in clinical treatment of respiratory system,urinary system,abdominal cavity infection,sepsis and other symptoms caused by sensitive bacteria.At present,the industrial production of cefminox sodium mainly adopts the batch crystallization,which has disadvantages such as low productivity,low product purity,product variability from batch to batch and unstable quality.In order to solve these problems,two continuous crystallization devices were constructed in the laboratory to systematically study the continuous crystallization process of cefminox sodium.Cefminox sodium single crystal was prepared by solvent volatilization method.Single crystal X-ray diffraction technology was used for single crystal analysis.The cell parameters,crystal system and space group of cefminox sodium were obtained.Diamond software was used to draw crystal structure and analyze the intermolecular forces in crystals.The molecules in the crystal of cefminox sodium are connected to form a three-dimensional network structure through Na-O1,Na-N6,and various hydrogen bonds.The metastable zone and induction time of cefminox sodium were determined by dynamic laser method,and the crystallization process was preliminarily determined by analyzing the data.The classical nucleation theory,single core model and multi-core model were used to fit the induction time data.Finally,kinetic parameters such as interfacial surface tension,critical nuclear radius and critical Gibbs free energy were calculated by the classical nucleation theory.Experimental crystallization shows that the metastable zone width increases with the increase of temperature,and the induction time decreases with the increase of suoversaturation ratio.Increasing supersaturation ratio is beneficial to crystal nucleation.The kinetics of continuous crystallization of cefminox sodium in mixed-suspension mixed-product removal(MSMPR)crystallizer and tubular crystallizer were studied by using the continuous steady-state method.The particle size distribution of crystal products after continuous crystallization system reaching steady state under different conditions was measured by Malvern particle size analyzer.Based on the grain size independent growth rate model,the nucleation and growth rates of cefminox sodium under different conditions were obtained.The nucleation kinetic equation and growth kinetic equation of cefminox sodium were obtained by fitting the data with 1st Opt software.It is found that in the continuous crystallization process of MSMPR,increasing supersaturation is more conducive to obtaining larger grain size crystals,while in the tubular crystallizer,high supersaturation is more conducive to crystal nucleation.Two different crystallizers were used for continuous crystallization experiments of cefminox sodium.The effects of different operating parameters on the yield,particle size,and crystal habit of the products from the MSMPR continuous crystallization process and the tubular crystallizer continuous crystallization process were investigated.The experimental results show that the optimized cefminox sodium product with MSMPR continuous crystallization has a narrower particle size distribution than the batched crystallization products,Dv(50)is about 164 μm,the yield is about 89.11%,and the crystal habit is complete.The particle size distribution of cefminox sodium product after continuous crystallization optimization in tubular crystallizer is the narrowest,Dv(50)is about 98 μm,the yield is about 76.84%,but the crystal habit is poor and the crystal agglomeration is serious.Therefore,the MSMPR continuous crystallization process is more suitable for producing cefminox sodium crystal products with large main crystal sizes and complete crystal habit.