设计空间法研究龙血竭酚类提取物的精制工艺(1)
[摘要]运用质量源于设计(QbD)理念，采用“设计空间”方法优化龙血竭酚类提取物的精制工艺。首先将龙血素B、7，4′二羟基黄酮含量及其转移率、总干膏收率等5个指标做为关键质量属性(CQA)，采用PlackettBurman设计实驗，发现关键工艺参数(CPP)为碱浓度、碱倍量和碱溶温度。再采用BoxBehnken设计建立CQA和CPP间的数学模型，方差分析显示模型P均小于005，失拟值均大于005，可以较好的描述CQA和CPP之间的关系。设定龙血素B、7，4′二羟基黄酮含量及其转移率、总干膏收率5个指标的控制限度，通过Monte Carlo仿真法计算获得基于概率的设计空间并验证。结果表明，优化后的纯化方法能够保证龙血竭酚类提取物精制工艺稳定，有助于提高酚类提取物批次间质量均一性，为生产自动化控制提供数据支撑。
[关键词]龙血竭酚类提取物； 精制工艺； 关键工艺参数； 关键质量属性； 设计空间
Studying on purification technology of Resina Draconis phenol
, 百拇医药
extracts based on design space method
ZHANG Jian1，3， ZHANG Xin2，3， BI Yuan2，3， XU Guihong2，3， HUANG Wenzhe2，3， WANG Zhenzhong2，3， XIAO Wei1，2，3*
(1. College of Pharmacy， Nanjing University of Chinese Medicine， Nanjing 210023， China；
2. Jiangsu Kanion Parmaceutical Co.， Ltd.， Lianyungang 222001， China；
3. State Key Laboratory of Pharmaceutical Process Newtech for Chinese Medicine， Lianyungang 222001， China)
, 百拇医药
[Abstract]The "design space" method was used to optimize the purification process of Resina Draconis phenol extracts by using the concept of "quality derived from design" (QbD) The content and transfer rate of laurin B and 7，4'dihydroxyflavone and yield of extract were selected as the critical quality attributes (CQA) PlackettBurman design showed that the critical process parameters (CPP) were concentration of alkali， the amount of alkali and the temperature of alkali dissolution Then the BoxBehnken design was used to establish the mathematical model between CQA and CPP The variance analysis results showed that the P values of the five models were less than 005 and the mismatch values were all greater than 005， indicating that the model could well describe the relationship between CQA and CPP Finally， the control limits of the above 5 indicators (content and transfer rate of laurine B and 7，4'dihydroxyflavone， as well as the extract yield) were set， and then the probabilitybased design space was calculated by Monte Carlo simulation and verified The results of the design space validation showed that the optimized purification method can ensure the stability of the Resina Draconis phenol extracts refining process， which would help to improve the quality uniformity between batches of phenol extracts and provide data support for production automation control
[Key words]Resina Draconis phenol extracts； refining process； critical process parameters； critical quality attributes； design space
龙血竭酚类提取物为中药5类新药龙血通络胶囊的原料药，具有活血化瘀通络之功效，可用于中风病经络(轻中度脑梗死)恢复期血瘀证。其有效部位总酚主要包括查耳酮类、黄酮类、黄烷类、色原酮类、茋类及简单酚类[1]，具有抗炎、镇痛、活血、止血、抗细菌、真菌、改变血液流变学等药理作用，其中7，4′二羟基黄酮、龙血素B具有抗血栓、抗血瘀、抗凝血、镇痛多重功效[2]。, 百拇医药(张建张欣毕宇安徐桂红黄文哲王振中萧伟)
[关键词]龙血竭酚类提取物； 精制工艺； 关键工艺参数； 关键质量属性； 设计空间
Studying on purification technology of Resina Draconis phenol
, 百拇医药
extracts based on design space method
ZHANG Jian1，3， ZHANG Xin2，3， BI Yuan2，3， XU Guihong2，3， HUANG Wenzhe2，3， WANG Zhenzhong2，3， XIAO Wei1，2，3*
(1. College of Pharmacy， Nanjing University of Chinese Medicine， Nanjing 210023， China；
2. Jiangsu Kanion Parmaceutical Co.， Ltd.， Lianyungang 222001， China；
3. State Key Laboratory of Pharmaceutical Process Newtech for Chinese Medicine， Lianyungang 222001， China)
, 百拇医药
[Abstract]The "design space" method was used to optimize the purification process of Resina Draconis phenol extracts by using the concept of "quality derived from design" (QbD) The content and transfer rate of laurin B and 7，4'dihydroxyflavone and yield of extract were selected as the critical quality attributes (CQA) PlackettBurman design showed that the critical process parameters (CPP) were concentration of alkali， the amount of alkali and the temperature of alkali dissolution Then the BoxBehnken design was used to establish the mathematical model between CQA and CPP The variance analysis results showed that the P values of the five models were less than 005 and the mismatch values were all greater than 005， indicating that the model could well describe the relationship between CQA and CPP Finally， the control limits of the above 5 indicators (content and transfer rate of laurine B and 7，4'dihydroxyflavone， as well as the extract yield) were set， and then the probabilitybased design space was calculated by Monte Carlo simulation and verified The results of the design space validation showed that the optimized purification method can ensure the stability of the Resina Draconis phenol extracts refining process， which would help to improve the quality uniformity between batches of phenol extracts and provide data support for production automation control
[Key words]Resina Draconis phenol extracts； refining process； critical process parameters； critical quality attributes； design space
龙血竭酚类提取物为中药5类新药龙血通络胶囊的原料药，具有活血化瘀通络之功效，可用于中风病经络(轻中度脑梗死)恢复期血瘀证。其有效部位总酚主要包括查耳酮类、黄酮类、黄烷类、色原酮类、茋类及简单酚类[1]，具有抗炎、镇痛、活血、止血、抗细菌、真菌、改变血液流变学等药理作用，其中7，4′二羟基黄酮、龙血素B具有抗血栓、抗血瘀、抗凝血、镇痛多重功效[2]。, 百拇医药(张建张欣毕宇安徐桂红黄文哲王振中萧伟)