【作者】 张春桃；

【导师】 王静康；

【作者基本信息】 天津大学 ， 化学工程， 2007， 博士

【摘要】 头孢曲松钠属于β-内酰胺类抗生素,是长效、广谱的第三代半合成头孢菌素,是国内外最畅销的抗感染药物之一。针对国产头孢曲松钠普遍存在的生产规模小、批间产品质量不稳定、结晶精制收率低等问题,本文对头孢曲松钠结晶过程进行了系统研究,为头孢曲松钠结晶精制工艺的工程放大和进一步深入研究提供了基础数据和理论依据,开发的头孢曲松钠溶析结晶新工艺已成功地应用于产业化生产。采用热分析法研究了头孢曲松钠的热不稳定性,建立了头孢曲松钠非等温TG脱水动力学模型,分析了两步脱水过程的最概然机理以及动力学补偿效应;采用Málek法建立了头孢曲松钠非等温DSC热降解动力学模型,模型计算值与实验值一致性好。在实验采集头孢曲松钠X-射线粉末衍射数据的基础上,应用JADE 4.0和分子模拟软件Cerius2确定了头孢曲松钠晶体的晶胞参数、所属晶系和空间群;基于能量最小化原理确定了头孢曲松钠晶体的空间结构;采用BFDH、AE模型预测了头孢曲松钠晶体的晶习,其中AE模型晶习与实际生长晶习更为相近,呈薄片状;考察了实际生长环境对晶习的影响规律。实验研究了头孢曲松钠结晶热力学性质,采用动态法测定了头孢曲松钠在6种单溶剂体系以及1种双组元溶剂体系中的溶解度,并分别采用经验方程和λh方程建立了头孢曲松钠在单溶剂体系和双溶剂体系中的溶解度模型;根据溶解度特性,筛选了溶剂系统,确定了头孢曲松钠溶析结晶方案;采用激光法测定了头孢曲松钠在A+S双组元体系中的介稳区。基于实验测定的结晶诱导期,估算了头孢曲松钠溶析结晶过程的固液表面张力、表面熵因子,初步推断晶体呈连续生长模式生长;采用分级法建立并求解了头孢曲松钠溶析结晶动力学方程;以粒数衡算方程为基础,结合质量衡算和动力学方程,建立了头孢曲松钠溶析结晶过程数学模型。依据晶体生长习性、介稳区特性、结晶动力学和过程模型模拟分析结果的预示,考察了晶种、结晶温度、结晶液初始浓度、溶析剂流加速率、搅拌强度、脱色活性炭用量等对结晶产品质量、粒度分布和收率的影响,建立了经验最佳操作时间表,达到了提高结晶产品质量、收率和粒度的效果。更多还原

【Abstract】 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.更多还原