Study On The Biological Enzyme Synthesis And Crystallization Process Of Cephradine

As a basic medicine listed in the Nation Essential Medicine of China,Cephradine,a first generation cephalosporin,is used in the treatment of respiratory tract infections,urinary tract infections,and soft tissue and skin structure infections and it has the potential to be utilized even more extensively.At present,the production of Cephradine mainly depends on chemical method where a variety of organic solvents are employed with tedious steps under strict reaction condition.The products after crystallization have many shortcomings such as severe environment pollution,low yield,and poor crystal habit.Besides,the particle is small in size,and uneven in particle size distribution.Based on the above background,the enzymatic method synthesis,crystallization thermodynamics,crystallization kinetics and crystallization process of Cephradine are studied deeply in this study.The preparation of Biological Enzyme Synthesis of Cephradine.The Enzymatic process is simple,the reaction condition is mild,and organic solvents are not used,,which is in accordance with the environmental protection policy of the coordinated development of Beijing-Tianjin-Hebei.Meanwhile,it reduces the toxic and side effects on the liver.In this study,the method of immobilized penicillin acylation enzyme catalytic 7-ADCA is adopted and double benzene methyl glycine cefepime hydrochloride is used to produce Cephradine.By using the single factor experiment method,the effect of raw material ratio,the reaction of stirring rate and the time to drip side chain on product yield and purity,are investigated.The optimal synthesis conditions are obtained and the yield and purity of the product are improved,with the quality yield coefficient reaching 150%and the purity higher than 98%.Study on the crystallization thermodynamics of Cephradine.A dynamic laser monitoring technique is used to determine the solubility and supersolubility of Cephradine with different temperature and pH value,two transformational theoretical models are elicited to correlate experimental data and the correlative model parameters are obtained.The data fits well with the two models,the equation of the relationship of the solubility and supersolubility of Cephradine with different pH value is obtained.The two new models also apply to other amphoteric antibiotics.Through further research,the distribution curves of the activity of species A~+,A~-,and A~±in the solution are obtained,which could provide theoretical basis for the study about the nucleation kinetics and industrial production.Study on the nucleation kinetics of Cephradine.The induction periods of Cephradine are investigated as a function of the supersaturation ratio.the metastable zone width with the changes of the temperature and pH are determined by combing with the thermodynamic data.By applying classical homogeneous nucleation theory,we deduce the crystal-liquid interfacial tension and the following fundamental nucleation parameters:the Gibbs free energy change for the formation of the critical nucleus,the radius of the critical nucleus,and the number of molecules in the critical nucleus,which could provide theoretical basis for the industrial production.Study on the crystallization process of Cephradine.By using the single factor experiment method,the effects of initial concentration,the speed rate of the liquid crystal material,stirring speed,the crystallization pH range,the quantity of seed crystal on the yield,crystal habit and particle size distribution of Cephradine,are investigated.The operating conditions of double feed crystallization are optimized,with the initial concentration 0.43,the speed rate of the liquid crystal material 2ml/min,the crystallization pH ranging from 2.5-2.7,and the quantity of seed crystal?0.1-1.0.Evenly rod-shaped crystal at a stirring speed of 140 r/min or homogeneous clusters at a stirring speed of 70r/min is obtained.In the above conditions,the crystallization products with good crystal habit and uniform particle size distribution is obtained.