Research On Water Extraction Process And Ethanol Precipitation Process Of Codonopsis Radix Based On QbD Concept

Quality by Design (QbD) concept focuses on product and processes understanding. According to QbD concept, drug quality can be improved by knowledge management and risk management. One of the important steps is to establish a design space in the implementation of QbD concept. The extraction process and the ethanol precipitation process of Codonopsis Radix were investigated based on QbD concept in this work. The main contents are summarized as follows:1. Optimization of the parameters of Codonopsis Radix extraction process using a design space approach. Total flavonoid yield, lobetyolin yield, pigment yield and dry matter yield were identified as the process critical quality attributes (CQAs). A risk assessment was applied to determine critical process parameters (CPPs), which were extraction temperature, extraction time, and the mass ratio of water and Codonopsis Radix (W/M ratio). Box-Behnken designed experiments were performed to build models between CPPs and process CQAs. A design space was calculated using a Monte-Carlo simulation method. Normal operation ranges to attain process CQA criteria are recommended as follows:extraction temperature of 88.9～92.0℃, extraction time of 1.50～1.90 h and W/M ratio of 7.80～8.60 mL/g. The verification experimental results agreed well with prediction results, which means that models are predictive and design space is reliable.2. Parameter optimization of first ethanol precipitation process of Codonopsis Radix using a design space approach. Total flavonoid recovery, dry matter removal and pigment removal were defined as the process CQAs. Plackett-Burman designed experiments were carried out to find the CPPs. Dry matter content of concentrated extract, the mass ratio of ethanol to concentrated extract and the concentration of ethanol were identified as the CPPs. Box-Behnken designed experiments were performed to establish the quantitative models between CPPs and CQAs. A probability based design space was obtained using a Monte-Carlo simulation method and verified. According to the verification results, the robustness of first ethanol precipitation process of Codonopsis Radix can be guaranteed by operating parameters within the design space. Recommended normal operation region is located in dry matter content of concentrated extract of 45.0～48.0%, amount of ethanol added of 2.48～2.80 g/g, and the concentration of ethanol of 92.0～92.7%.3. Development of feedforward control strategy for second ethanol precipitation process of Codonopsis Radix. The contents of total flavonoid, pigment, fructose, glucose and sucrose in the dry matter of concentrated supernatants of first ethanol precipitation were determined as attributes of the concentrate. The concentrations of the dry matter, total flavonoid, pigment, fructose, glucose and sucrose were considered as the quality indices of the second ethanol precipitation supernatants. Mathematical models relating concentrate attributes, process parameters and supernatant quality indices were developed. According to the attributes of a new concentrate, the operation ranges of parameters can be calculated. The results of verification experiments agreed well with prediction results. Feedforward control of process parameters can improve batch-to-batch consistency of supernatants.