【作者】 王波；

【导师】 王学重；

【作者基本信息】 华南理工大学 ， 化学工程， 2017， 硕士

【摘要】 手性药物的光学纯度和稳定性是其产品质量的重要指标。在众多手性拆分的方法中,结晶法因其操作简便,经济,一直是人们关注和研究的热点。本文以抗高血压药物缬沙坦为例,研究了利用优先结晶拆分高共熔点组成的外消旋化合物缬沙坦的过程,并利用诱导结晶工艺改善了其药物的稳定性。具体内容如下:利用质量法分别测量了不同对映体含量的缬沙坦在乙酸乙酯和混合溶剂(乙酸乙酯:乙醇=99%:1%,m:m)中的溶解度,根据得到的溶解度数据分别绘制了缬沙坦在两种溶剂体系中的溶解度三元相图。对比两种溶剂体系中的三元相图,判断外消旋体缬沙坦属于外消旋化合物,且其共熔点组成为S:R(R:S)=90%:10%。此外,测量了91%(S)-V(表示对映体(S)-缬沙坦的摩尔含量为91%)在两种溶剂体系中的溶解度和介稳区,用于设计和实施优先结晶工艺。根据三元相图确定了待优化纯度为91%(S)-V的初始浓度,并成功在两个溶剂体系中分别实施优先结晶,得到了光学纯度大于99%的产品。对比两个体系中的实验结果,在混合溶剂中收率更高,且操作区域更大,更易实现优先结晶,确定混合溶剂为该药物优先结晶的较适宜溶剂体系,说明溶剂的选择对药物的手性拆分影响重大。此外,根据三元相图理论,提出一种用于快速拆分外消旋化合物的结晶优化方法。在1L反应釜中研究了自发结晶,诱导结晶,反溶剂结晶和造粒工艺对药物缬沙坦原料药稳定性的影响,然后在5L反应釜中放大诱导结晶工艺研究其制剂适应性。即将缬沙坦原料药按照配方做成胶囊剂型,做三个月加速稳定性试验研究其化学稳定性。同时将缬沙坦原料药按照配方做成分散片剂型,研究其崩解速率。最终确定诱导结晶工艺生产的缬沙坦原料药适用于胶囊剂型和分散片剂型的制作。研究了几种过程分析技术在结晶过程中的应用。在本文的结晶研究中,将在线红外,浊度计和在线二维成像应用于结晶过程的研究,并取得了良好的成果,说明了过程分析技术对结晶过程的重要性,应该大力发展其在结晶过程中的应用。更多还原

【Abstract】 The optical purity of chiral drug is one of the important product qualities.Among the various methods of enantioseparation,crystallization is one of the most attractive as it is simple and economical.In this dissertation,we take valsartan as an example to study the preferential crystallization for the separation of high-eutectic racemic compound,and to study the seeding crystallization to improve the stability of valsartan.The details are as follows:The solubility of valsartan with different optical purity in ethyl acetate and mixed solvent(ethyl acetate : ethanol=99%:1%,m:m)was measured by gravimetric method.And the ternary phase diagrams of valsartan in two solvent systems were constructed using the solubility data.The racemate valsartan was identified to be racemic compound from the ternary phase diagrams,and its eutectic point is S/R(R/S)=90%:10%.Besides,the solubility and MSZW of 91%(S)-V in two solvent systems were measured for the preferential crystallization.The initial concentration of 91%(S)-V for preferential crystallization was obtained from the ternary phase diagrams,and product with optical purity above 99% was gained by preferential crystallization from the two solvent systems,respectively.The mixed solvent system was determined to be the better solvent system of valsartan to perform preferential crystallization for its higher yield and higher success rate.This indicates that solvent have an important effect on the enantioseparation of chiral drugs.And an approach for rapid optimization of the preferential crystallization condition based on theory and experiments to obtain optically pure enantiomer products was presented.The effect of spontaneous crystallization,seeding crystallization,anti-solvent crystallization and granulation on stability of valsartan was studied in 1L reactor.The product obtained by seeding crystallization was to study the preparation adaptability.Then the product was prepared to capsule and dispersible tablet to test its chemical stability by accelerated stability test and its disintegration rate,respectively.Finally the seeding crystallization process was tested to be the suitable one for capsule and dispersible tablet.Application of process analytical technique(PAT)on crystallization was studied.On-line FTIR,turbidimeter and on-line 2D imaging system were applied to the crystallization of valsartan in this dissertation,and achieved good results,which indicates its importance for crystallization,and should be developed.更多还原