【作者】 张扬；

【导师】 钱宇； 江燕斌； X.Z.Wang；

【作者基本信息】 华南理工大学 ， 化学工程， 2010， 博士

【摘要】 蒿甲醚是一种大环内酯结构的活性药物组分,被世界卫生组织推荐为疟疾治疗的专用药。结晶是蒿甲醚生产的关键过程,纯度、晶形、多晶型、粒度及粒度分布是蒿甲醚产品的关键质量控制指标,影响其生产过程的下游工艺操作及其产品的生物利用度。本文在充分调研的基础上,通过热力学和动力学实验,结合过程分析技术,对蒿甲醚结晶过程进行了系统的应用基础研究。本文采用重量法测定了蒿甲醚在7种有机溶剂体系和乙醇-水、甲醇-水双组元溶剂体系的溶解度数据,研究了溶解度与温度和溶剂组成之间的关系,并采用理想溶液模型和经验方程lnx=A+BT+CT2,建立了蒿甲醚在7种有机溶剂体系和乙醇-水、甲醇-水双组元混合溶剂体系的溶解度模型。基于多晶型筛选实验开展了对蒿甲醚多晶型的研究,通过X射线粉末衍射和X射线单晶衍射表征,结合分子动力学模拟对所确定的两种蒿甲醚多晶型进行了分析,结果表明,其晶胞结构分别为单斜晶系、P21空间群和三斜晶系、P-1空间群,并分别采用AE模型和BFDH模型对蒿甲醚的晶习进行了模拟预测。过饱和度是结晶过程的推动力,决定晶体的成核与生长过程。本文采用UV-Vis光纤光谱仪和自行设计的装置,结合正交信号校正技术,对蒿甲醚的UV-Vis光谱数据进行了预处理和模型化,并建立了蒿甲醚在乙醇-水抗溶剂结晶过程的UV-Vis在线浓度检测方法。结果表明,该模型和检测方法具有较强的实用性。本文采用在线浊度仪研究了蒿甲醚乙醇-水混合体系抗溶剂结晶过程的亚稳区,建立了亚稳区宽度预测模型。采用在线聚焦激光反射测量仪研究了蒿甲醚抗溶剂结晶过程的成核与生长,结合矩量法,对蒿甲醚抗溶剂结晶过程动力学的实验数据进行了分析和回归,得到了蒿甲醚抗溶剂结晶过程的动力学参数。最后,本文采用冷热台显微观测系统,研究并确定了蒿甲醚抗溶剂结晶过程蒿甲醚晶体的生长方式。上述研究结果,将为蒿甲醚生产中的抗溶剂结晶过程提供必要的基础数据。更多还原

【Abstract】 β-artemether is an important macrocyclic lactone active pharmaceutical ingredient, and recommended by WHO for treating of malaria. Crystallization is the crucial process for separation and purification ofβ-artemether. Purity, crystal shape, polymorphism, and crystal size distribution (CSD) are crucial product quality factors, and these factors greatly impact both downstream processing and bioavailability ofβ-artemether product. In this study, after considerable investigation, thermodynamics and kinetics experiments were conducted for systematic studies ofβ-artemether crystallization using process analytical technology.In this work, the solubilities ofβ-artemether in seven organic solvents, ethanol + water, and methanol + water solvent mixtures were measured using the gravimetric method, and the experimental solubility data were correlated with empirical equation and idea solution model, models for prediction of solubility were developed.Polymorphism ofβ-artemether was investigated, and two crystal structures ofβ-artemether were confirmed using X-ray powder diffraction technique, X-ray single crystal diffraction technique, and molecular kinetics simulation method. One is monoclinic crystal with spacegroup of P21, the other is triclinic crystal with spacegroup of P-1. The crystal habit ofβ-artemether was predicted based on AE model BFDH model.Supersaturation is the driving force of crystallization, which determines nucleation and crystal growth. The method for on line measurement of solution concentration was developed successfully. In this method, UV-Vis fiber spectroscopy coupled with a circulated system was designed for acquiring of raw UV-Vis spectra, and the model for prediction of solute concentration was developed based on OSC corrected UV-Vis spectra.The metastable zone width (MSZW) was measured by on line turbidimeter, and the calibrated model for prediction of MSZW was developed. The nucleation and crystal growth were investigated using Focused Beam Reflectance Measurement (FBRM), the experimental kinetics data were analyzed and calibrated by moment method, and the parameters for kinetics equation were obtained based on experimental kinetics data.The crystal growth mechanism was confirmed according to the findings observed using the hot stage camera system.Research results of this study would provide the fundamental data for the manufacturing ofβ-artemther.更多还原