基于质量源于设计理念的热炎宁合剂提取工艺优化及提取过程评价研究  

Extraction process optimization and link evaluation of Reyanning Mixture based on quality by design idea

作　　者：张颖[1] 邱金清 魏玄 雷璇 唐莹莹 屈琼 赵小梅 张新博 孙静[1] 罗伟 宋逍[1,2] ZHANG Ying;QIU Jin-qing;WEI Xuan;LEI Xuan;TANG Ying-ying;QU Qiong;ZHAO Xiao-mei;ZHANG Xin-bo;SUN Jing;LUO Wei;SONG Xiao(Shaanxi University of Chinese Medicine,Xianyang 712046,China;Engineering Research Center for Pharmaceutics of Chinese Materia Medica and New Drug Development,Ministry of Education,Beijing 100029,China;Tsinghua Deren Xi'an Happiness Pharmaceutical Co.,Ltd.,Xi'an 710043,China)

机构地区：[1]陕西中医药大学,陕西咸阳712046 [2]中药制药与新药开发教育部工程研究中心,北京100029 [3]清华德人西安幸福制药有限公司,陕西西安710043

出　　处：《中国中药杂志》2024年第12期3229-3241,共13页China Journal of Chinese Materia Medica

基　　金：陕西省教育厅项目(21JC011);陕西省中医药管理局项目(2021-04-ZZ-007);国家重点研发计划项目(2019YFC1711204)。

摘　　要：热炎宁合剂是“秦药”优势中成药品种之一,该研究基于质量源于设计(quality by design, QbD)理念,对热炎宁合剂的提取工艺进行优化研究,以咖啡酸、虎杖苷、大黄素和白藜芦醇为关键质量属性(critical quality attributes, CQAs),采用Plackett-Burman试验确定料液比、提取温度和提取时间为关键工艺参数(critical process parameters, CPPs),通过星点设计-效应面法试验设计建立数学模型,构建设计空间并验证,获取热炎宁合剂最优的提取工艺为料液比11.84 g·mL^(-1)、提取温度81℃、提取2次。在最佳提取工艺下采用近红外光谱法(near infrared spectroscopy, NIRS)结合高效液相色谱法(HPLC)建立提取过程中CQAs的偏最小二乘法(partial least-square, PLS)定量模型,结果显示,4个CQAs定量模型的校正集相关系数(R_c)和验证集相关系数(R_p)均超过0.9,校正集均方根误差(RMSEC)分别为0.744、6.71、3.95、1.53μg·mL^(-1),验证集均方根误差(RMSEP)分别为0.709、5.88、2.92、1.59μg·mL^(-1)。表明该研究优化得到的热炎宁合剂提取工艺合理、可行且稳定可靠,所建立的NIRS定量模型具有良好的预测性,可用于提取过程中CQAs含量的快速测定,可为热炎宁合剂的工艺研究及质量控制提供实验基础。Reyanning Mixture is one of the superior Chinese patent medicine varieties of"Qin medicine".Based on the idea of quality by design(QbD),the extraction process of the Reyanning Mixture was optimized.The caffeic acid,polydatin,resveratrol,and emodin were used as critical quality attributes(CQAs).The material-liquid ratio,extraction temperature,and extraction time were taken as critical process parameters(CPPs)by the Plackett-Burman test.The mathematical model was established by the star designeffect surface method,and the design space was constructed and verified.The optimal extraction process of the Reyanning Mixture was obtained as follows:material-liquid ratio of 11.84 g·mL^(-1),extraction temperature at 81℃,and two extractions.A partial least-square(PLS)quantitative model for CQAs was established by using near-infrared spectroscopy(NIRS)combined with high-performance liquid chromatography(HPLC)under the optimal extraction process.The results showed that the correlation coefficients of the correction set(Rc)and validation set(Rp)of the quantitative models of four CQAs were more than 0.9.The root mean square error of the correction set(RMSEC)were 0.744,6.71,3.95,and 1.53μg·mL^(-1),respectively,and the root mean square error of the validation set(RMSEP)were 0.709,5.88,2.92,and 1.59μg·mL^(-1),respectively.Therefore,the optimized extraction process of the Reyanning Mixture is reasonable,feasible,stable,and reliable.The NIRS quantitative model has a good prediction,which can be used for the rapid content determination of CQAs during extraction.They can provide an experimental basis for the process research and quality control of Reyanning Mixture.

关 键 词：质量源于设计 热炎宁合剂 关键质量属性 关键工艺参数 近红外光谱 

分 类 号：R284.2[医药卫生—中药学]