【作者】 高晓燕；

【导师】 乔延江；

【作者基本信息】 北京中医药大学 ， 中药学， 2006， 博士

【摘要】 目的:制药生产在线检测及控制是对过程数据实时采集、传输、处理及建模的整合,以达到对生产过程中各环节影响质量的因素进行控制,保证产品稳定、均一。实现生产过程中的在线质量控制是中药质量控制的发展方向。本研究以清开灵注射液的生产为载体,确定其过程的关键环节,对各中间体及成品建立适合于在线检测的快速质量判断方法,为清开灵注射液的在线质量控制提供方法学依据。方法:清开灵注射液的处方组成为:胆酸、猪去氧胆酸、珍珠母、板蓝根、水牛角、黄芩苷、栀子、金银花等。采用不同测试技术间的相关分析建立指标成分的快速定量方法;采用UV光谱相似度比较建立整体性、均一性的快速判断方法。对各中间体及成品的快速质量评价方法如下:一、本文比较了3种方法快速测定水解液、板兰根提取液中总氮含量:①改良的茚三酮比色法反应条件:样品初始pH=8.0,沸水浴6min,2%茚三酮溶液1mL,pH=8.0的缓冲液0.5mL。根据茚三酮反应后的UV光谱,选择相关性较好的波长点,建立总氮含量的预测方程;②总炭/总氮(TOC/TN)法燃烧炉温度为720℃,TNM-1单元流速为500mL?min-1,载气为高纯空气,检测器为化学发光检测器;③NIR光谱法水解液和板蓝根提取液均采用原始光谱,数据处理方法均为逐步多元线性回归(SMLR),测定水解液选择的波数点为6608.86cm-1和7170.04cm-1,测定板蓝根提取液选择的波数点为7160.4cm-1和7166.18 cm-1。二、栀子提取液的快速质量评价: HPLC测定多批栀子提取液中栀子苷的含量,确定判别栀子提取液质量的栀子苷含量范围,选择栀子提取液的UV光谱中和栀子苷含量相关性最好的波长点,采用相关分析法建立栀子苷含量的预测方程,根据预测结果及范围判别栀子液的质量。三、金银花提取液的快速质量评价:HPLC测定多批金银花提取液中绿原酸的含量,确定判别金银花提取液质量的绿原酸含量范围,选择和绿原酸含量相关性最好的UV光谱类型和波长,采用相关分析的方法建立绿原酸含量的预测方程,根据预测结果及绿原酸的含量范围判别金银花提取液的质量。四、四混液的快速质量评价:1、NIR光谱法预测总氮及栀子苷含量选用原始光谱,数据处理方法为SMLR,总氮含量预测模型的光谱为7185.47和5384.28 cm-1,栀子苷含量预测模型的波数点为5372.71cm-1和4362.19cm-1;2、UV光谱的相似度比较判断整体性及均一性以四混液中总氮和栀子苷含量的上下限为依据,配制具有代表性的四混液,测定UV光谱,比较相似度,确定合格四混液的相似度范围,建立质量判断模型。五、胆酸混合液的快速质量评价:考察乙醇浓度对胆酸、猪去氧胆更多还原

【Abstract】 Objective: Online process monitoring and control of pharmaceutical manufacturing processes are systems for design, analysis, and control of manufacturing processes, based on timely measurements of critical quality and performance attributes of raw and in-process materials and products, to assure stability and homogeneity of products at the completion of manufacturing. Implementing online quality control of the medicines production is the trend of traditional Chinese medicines standard. In this study, Qingkailing injection was selected as an example to develop rapid quality evaluation methods. The key steps in the production process were confirmed. The quick quality appraisal methods of the intermediates and the preparation were established. All these provided the base of methodology of online quality control of qingkailing injection.Methods: The formula of Qingkailing injection is composed of cholic acid, hyodeoxycholic acid, Concha Margaritifera, Radix Isatidis, Cornu Bubali, baicalin, Fructus Gardeniae, and Flos Lonicerae Japonicae. The correlation analysis between different measuring and testing techniques was used to quickly determine the marker and active ingredients; Comparison of similarity degree of UV spectra was used to evaluate the integerity and homogeneity.Ⅰ. Three kinds of methods of determining the content of total nitrogen (TN) of the hydrolyzed solution and the aqueous solution of Radix Isatidis extraction (ASRIE) were compared.①Improved ninhydrin colorimetry. The reaction conditions includes adjusting the pH of the prime sample to 8, adding 2% aqueous solution of ninhydrin 1mL and pH=8 buffer 0.5mL, and heating the samples in the boiling water for six minutes. The best correlating wavelength was selected to bulid the model for predicting the content of TN.②Total organic carbon / Total nitrogen determination (TOC/TN). Analyzer and its option unit TNM-1(Total Nitrogen Measurement) were used to measure the TN content in the Qingkailing injection and its intermediate products. High purity air was used as carrier gas at a flow rate of 150mL?min-1. The temperature of combustion tube was 720℃. Chemical luminescence detector was selected.③NIR spectrometry. The conditions of establishing the model for predicting the TN content of the hydrolyzed solution: Original spectrum was selected. Stepwise multiple linear regression (SMLR) was used to data process. The selected wavenumbers were 6608.86 cm-1 and 7170.04 cm-1; the conditions of establishing the model for predicting the TN content of ASRIE: Original spectrum was selected, and SMLR was used as a data processing method.更多还原