Studies On Application Of QbD In Extraction And Ethanol Precipitation Process Analysis Of Danhong Injection

The concept of quality by design (QbD) has been widely accepted and applied in the pharmaceutical manufacturing industry. Danhong injection is made from Salviae miltiorrhizae Radix et Rhizoma (Danshen) and Carthami Flos (Honghua) after a series of processes, including water extraction, concentration, ethanol precipitation, and adsorption. The extraction process extracts amount of active ingredients and highly polar impurities while ethanol precipitation process removes highly polar impurities in the concentrated extract, such as saccharides, salts, and proteins. However, the losses of active ingredients, including phenolic acids and flavonoids, are also observed in published works. The quality of extraction and ethanol precipitation affect the effects of later processes and the quality of drugs. Therefore it is urgent to investigate the process of extract and ethanol precipitation for better optimization and control.In this paper, Danhong extraction and ethanol precipitation were used as examples to inverstigate the application of QbD in the manufacturing process of Danhong injection. The main contents and achievements of this thesis are summarized as follows:1. Risk assessment of Dahong extraction and ethanol precipitation process. A number of factors may impact the performance of extraction and ethanol precipitation. Risk assessment can be used to obtain critical quality attributes (CQAs) and critical process paramaters (CPPs). According to the risk analysis, for the extraction process, extraction time, extraction times, and the quantity ratio of water and material, are identified as CPPs while the amount of dry matter extracted and the amount of five active ingredients extracted are chosen as CQAs. For the ethanol precipitation process, refrigeration temperature, concentration of ethanol added, water content of concentrated extract, and amount of ethanol added, are investigated as CPPs while dry matter removal and five active ingredients recovery are indetified as CQAs.2. A design space of extraction process of Danhong extraction process was developed using the Monte Carlo method. The effects of different Monte Carlo simulation conditions were discussed.3. In the process of Danhong ethanol precipitation, some CPPs are difficult to be controlled in a narrow range, such as refrigeration temperature, while some CPPs can be easily controlled, including concentration of ethanol added, water content of concentrated extract, and amount of ethanol added. Experimental design was applied to establish quantitative relationships among adjustable parameters, the noise parameter, and CQAs of the ethanol precipitation process. The probability to attain the defined criteria is calculated using the Monte Carlo method. A design space is obtained and verified using adjustable parameters to control the effects caused by noise parameter fluctuation.