【作者】 张海涛；

【导师】 王静康；

【作者基本信息】 天津大学 ， 化学工程， 2008， 博士

【摘要】 针对我国制药工业头孢噻肟钠生产中存在的产品纯度低,分离困难且结晶过程中易聚结成胶等问题,本工作对其精制结晶技术进行了系统化研究,开发出了新型头孢噻肟钠结晶技术,制备出了符合欧美国际质量水平要求的头孢噻肟钠结晶产品。头孢噻肟钠为第三代头孢类半合成广谱抗菌素,当前仍有着广泛的国内外市场前景。本研究中,采用显微镜实时观测、X射线粉末衍射(powder-XRD)、扫描电镜(SEM)、红外光谱(FT-IR)等测试手段对头孢噻肟钠结晶过程中出现的成胶现象以及聚结现象进行了分析。并通过调节pH值、设定结晶温度程序以及添加晶种等手段,有效消除了上述现象对结晶过程的影响。在实验采集头孢噻肟钠晶体X-射线粉末衍射数据的基础上,应用分子模拟软件Cerius2确定了晶胞参数、所属晶系和空间群;基于能量最小化原理确定了空间结构;进而采用BFDH、AE模型预测晶体晶习,并与实验产品进行了对比。采用动态法考察了头孢噻肟钠在17种纯溶剂中的溶解度,并详细测定了其在5种纯溶剂中的溶解度。根据溶解度特性及产品性能分析,筛选了溶剂系统,建立了纯溶剂中头孢噻肟钠的溶解度模型。动态法测定了不同温度和溶剂配比下,头孢噻肟钠在“水+S溶剂”二元溶剂体系中的溶解度,根据经验方程、λh方程和CNIBS/Redlich-Kister方程建立了二元溶剂体系中的溶解度模型。测定了头孢噻肟钠溶析结晶的介稳区和诱导期,根据初级成核理论计算了固液表面张力、表面熵因子。结合原子力显微镜(AFM)测定结果,推断晶体表面生长为连续生长机理;借助聚焦光束反射测量仪(FBRM)、颗粒成像测量仪(PVM)、Malvern Mastersizer粒度分析仪、扫描电子显微镜(SEM)及显微镜实时观测等手段对溶析结晶过程中的成核、生长及二次过程进行了分析。应用间歇动态法测定了头孢噻肟钠溶析结晶过程中的动力学数据。按粒度相关生长模型建立了其结晶动力学方程组,确定了结晶过程中晶体生长速率方程以及二次成核速率方程中的相关参数。在结晶热力学、结晶动力学以及结晶过程分析的基础上,建立了头孢噻肟钠结晶工艺过程数学模型。实验考察了各种操作参数对产品质量和收率的影响,得到头孢噻肟钠优化结晶工艺操作时间表。针对头孢噻肟钠结晶产品粒度较小的缺点,开发了球形结晶新工艺。该工艺在保障产品质量的前提下,通过结晶母液中颗粒间的相互作用得到可控粒度的球形聚结产品,可有效改进过滤、运输、贮存,制剂等后续处理工艺。该技术尚可应用于其他药物及生物产品的结晶过程中。以上有关研究内容尚未见文献报道。更多还原

【Abstract】 In order to resolve the problems indwelling the industrial crystallization of cefotaxime sodium, such as low purity of the crystal product, difficult separation and the gelation & agglomeration phenomena in the process of crystallization, the investigation on the crystallization of cefotxime sodium has been performed. By means of the new crystallization technology developed in this work, the product, which is up to the standard, has been successfully synthesized.Cefotaxime sodium, which belonges toβ-lactam antibiotics, is a third generation, semisynthetic, broad-spectrum cephalosporin, and has still a wide market prospect at home and abroad at present. In the current work, by means of real-time observation by microscope, powder-XRD, SEM and FT-IR technology, the gelation andagglomeration phenomena in the process of crystallization have been investigated, and their effects on the crystallization process have been efficiently avoided by means of regulating the pH value of the mother solution, adjusting the crystallization temperature program and seeding, etc.By Cerius2, the crystal cell parameters, crystal system and space group of cefotaxime sodium were simulated. At first, possible space groups of cefotaxime sodium can be obtained by indexing its experimental X-ray power diffraction pattern. Subsequently, the crystal structure was determined based on the energy minimization principle; and the crystal habit was predicted by employing BFDH and AE models. The solid-liquid equilibrium behavior of cefotaxime sodium in 17 solvents was investigated, and the solubilities in 5 good solvents were determined by dynamic method. The model equations in pure solvents were established, and then the crystallization solvent system was selected according to solubility and products properties. The solubilities of cefotaxime sodium in water + S binary mixtures were also measured by dynamic method. And different model equations, such as empirical equation,λhequation and CNIBS/Redlich-Kister equation, were employed to correlate the solubility data.The metastable zone and induction time of crystallization were determined by laser monitoring method and the effects of operation conditions such as temperature, agitation and addition rate of dilute agent were examined. The solid-liquid surface tension and surface entropy factors were estimated based on primary nucleation theory. Combining with the surface morphology acquired by AFM (Atomic Force Microscopy), the growth mechanism of crystal surface was deduced as continuous growth. FBRM (Focused Beam Reflectance Measurement), PVM (Particles Visual Measurement), Malvern Mastersizer and SEM (Scanning Electronic Microscopy) etc were employed to investigate the nucleation, growth and secondary processes in the process of crystallization.Batch dynamic method was used to research the drowning-out crystallization kinetics behavior of cefotaxime sodium. The crystallization kinetic equations were established with size-dependent growth rate model and the correlation parameters of secondary nucleation and crystal growth rate equations were determined.Based on the investigation of the crystallization thermodynamics, kinetics and analysis of crystallization technique, the mathematical model of the drowning-out crystallization process was established according to the population balance equations and mass balance equations. The effects of operation conditions on the crystallization process and the quality of product were investigated in detail by both experiments and model simulation, and the optimal operation strategy was established.The new spherical crystallization technology was developed ascribing to the properties of the small crystal size and morphology of the cefotaxime sodium. On the premise of ensuring the quality of the product, the spherical agglomerated particles can be obtained by this technology, and the post-treatment procedures, such as filtration, transport, storage and granulation etc, can be efficiently improved. This technology can be applied in crystallization procedure of other pharmaceutical and biology products.No same report to above study results has been published in literature up to date.更多还原