Studies On Optimization And Control Methods For The Extraction And Ethanol Precitation Processes Of Salviae Miltiorrhizae Based On Quality By Design

With the progress of modernization and internationalization of traditional Chinese medicine (TCM), producing high quality products is the common requirement of both national and international drug regulatory institutions. However, the level of the manufacturing process of TCM products currently is low due to the lack of process optimization and control technologies, which have seriously restricted the improvement of final product quality. Recently, the concept of quality by design (QbD) has been widely accepted by international pharmaceutical industry, and successfully applied to the process development of chemical drug products, which have laid the foundations for the quality promotion of chemical drug products. For this reason, taking extraction and ethanol precipitation processes of Radix Salviae Miltiorrhizae (Danshen) as examples, studies on the optimization and control methods for the manufacturing process of TCM products based on QbD were carried out, which aimed to improve the level of the manufacturing process of TCM products. The major contents and achievements of this dissertation are summarized as followings:1. The solubilities of four compounds contained in Danshen, which were protocatechuic aldehyde, caffeic acid, galactose, and raffinose pentahydrate in the mixtures of ethanol-water at the temperatures of 273.2 to 303.2 K were determined. The models used for predicting the solubilities of caffeic acid and galactose were established. The measured solubility data provides information to further investigate the ethanol precipitation process of Danshen.2. Based on the concept of QbD, risk analysis and design of experiment were applied to screen critical process parameters (CPPs) of the first and the second ethanol precipitation processes of Danshen. The relationships between CPPs and process performance were established. The operating conditions of the second ethanol precipitation were optimized, and the design space of the first ethanol precipitation was constructed. Finally, the control strategy for ethanol precipitation process was proposed.3. The relationships of the process parameters of Danshen extraction and ethanol precipitation with the antioxidant activity of intermediates were investigated, and relevant regression models were established. Taking antioxidant activity as criterion, the design space of extraction process was established, and the operating conditions of ethanol precipitation were optimized. This research can be useful to develop the bioassay-guided optimization and control methods for the manufacturing process of TCM products.4. A control method for the extraction process was established based on the investigation of the relationships among the quality attribute of Danshen raw materials, process parameters and extract quality. Through this method, process parameters can be set according to the quality attribute of Danshen raw materials, which is helpful to improve the batch-to-batch quality consistency of finished products. Furthermore, an approach to set the range of the quality indexes of raw materials was proposed, which help to control input raw materials during TCM industrial production.5. Combining UV-vis spectroscopy with chemometrics, a method for determining antioxidant activity was established using DPPH scavenging assay as index, and was applied to predict the antioxidant activity of the intermediate from ethanol precipitation process of Danshen. The proposed method provides a reference for the rapid analysis of the antioxidant activity of intermediates in the process of TCM products.