Study On Dilution Crystallization Process Of Ceftriaxone Sodium

Ceftriaxone sodium, which belonges toβ-lactam antibiotics, is a third generation, semisynthetic, broad-spectrum cephalosporin, and has been one of the most salable anti-infectious drugs home and abroad. Systematic studies have been performed to resolve the problems occurred in the home industry manufacture of ceftriaxone sodium, such as little manufacture scale, significant quality difference between batches, low yield. The results that served as the basic data and important foundation for scaling up and further research on crystallization of ceftriaxone sodium were achieved. A new process of dilution crystallization has been successfully used for industry manufacture of ceftriaxone sodium, and the product quality, yield and size were enhanced much more than that of the old technology.The non-isothermal dehydration process of ceftriaxone sodium was systematically studied through Thermogravimetry (TG). The kinetics and the most probable mechanism functions of the two dehydration steps were achieved. The non-isothermal decomposition model of ceftriaxone sodium was also achieved through Differential Scanning Calorimetry (DSC) by Málek method, and the consistency between the experimental data and the values predicted by model is good.Based on the X-ray powder diffraction data collected experimentally, the crystal cell parameters, crystal system and space group of ceftriaxone sodium were simulated by using JADE 4.0 and Cerius2. The crystal structure was determined on the basis of the energy minimization principle; and the crystal habit was predicted by using BFDH law and AE law, of which the habit predicted by AE law is plate and is more similar to the actual habit grown from solution. The effects of growing conditions on crystal habit were also experimentally studied.The solubilities of ceftriaxone sodium in different solvents were measured by the dynamic method. The empirical equation and theλh equation were used to correlate the solubility data in pure solvent and mixed system respectively, and good results were achieved. Based on the solubility characteristics, the solvent system for crystallization process was screened out, and the dilution crystallization was chosen to separate and purify ceftriaxone sodium. The metastable zone for dilution crystallization of ceftriaxone sodium in A+S system was also experimentally studied by laser method. Based on the induction period determined experimentally, the surface tension and surface entropy factors of the dilution crystallization process of ceftriaxone sodium were estimated, which indicated a continuous growth model. The nucleation, size-dependent growth and agglomeration kinetics in the dilution crystallization process of ceftriaxone sodium were established through the classes method. Together with the crystallization kinetics and the mass balance equations, the dilution crystallization process of ceftriaxone sodium was simulated on the basis of the population balance.According to the researches of the crystal growth habit, metastable zone characteristics, crystallization kinetics and process simulation analysis, the effects of seeds, temperature, initial concentration of mother liquor, addition rate of anti-solvent, etc, on the crystal size distribution and yield were experimentally studied in detail. The optimum operation schedule for the dilution crystallization of ceftriaxone sodium has been determined, and the product quality, yield and size are enhanced obviously.