基于质量源于设计理念的复方蜘蛛香醇提工艺研究

目的:运用质量源于设计(quality by design，QbD)理念，优化复方蜘蛛香醇提工艺。方法:以复方蜘蛛香为模型药，木香烃内酯(costunolide，CL)、去氢木香内酯(dehydrocostus lactone，DCL)、橙皮苷(hesperidin，HSP)和出膏率为关键质量属性(critical quality attributes，CQAs)，采用危害及可操作性分析法对复方蜘蛛香醇提工艺进行风险评估，采用单因素实验设计确定各因素的高低水平，Plackett-Burman实验设计筛选出关键工艺参数(critical process parameters，CPPs)，采用Box-Behnken优化醇提工艺，建立多个指标重叠的设计空间，选取较优操作空间进行工艺验证。结果:筛选的关键工艺参数为料液比、乙醇体积分数和提取次数，为方便实验操作，最终选择的提取工艺为:料液比1∶10，乙醇体积分数60%，提取次数2次，在该工艺条件下，复方蜘蛛香提取液能够达到木香烃内酯≥18.0 mg·g^-1，去氢木香内酯≥15.0 mg·g^-1，橙皮苷≥2.5 mg·g^-1，出膏率≥30.0%。结论:通过QbD理念开发的复方蜘蛛香醇提工艺有助于提高产品质量，为其制剂的工艺开发及质量控制提供实验基础。

Study on alcohol extraction technology of Compound Zhizhuxiang based on quality by design

OBJECTIVE The alcohol extraction process of compound spider fragrance was optimized by using the concept of quality by design(QbD).METHODS Taking CZ as model drug,costunolide(CL),dehydrocostus lactone(DCL),hesperidin(HSP)and paste yield as critical quality attributes(CQAs),the risk assessment of ethanol extraction process of CZ was evaluated by hazard and operability analysis.The Single factor experimental design was used to determine the level of each factor,Plackett-Burman design was used to screen out critical process parameters(CPPs),Box-Behnken was used to optimize the ethanol extraction process,a design space with multiple indexes overlapping was established,and a better operation space was selected for process verification.RESULTS The CPPs were solid-liquid ratio,ethanol volume fraction and extraction times.For the convenience of experimental operation,the design space of extraction process was finally selected as follows:solid-liquid ratio was 1:10,ethanol volume fraction was 60% and extraction times were twice.Under these conditions,Compound Zhizhuxiang extract can reach costunolide ≥ 18.0 mg·g^-1,dehydrocostunolide ≥ 15.0 mg·g^-1,hesperidin ≥ 2.5 mg·g^-1,and the paste yield ≥ 30.0%.CONCLUSION The alcohol extraction process of Compound Zhizhuxiang developed through QbD concept is helpful to improve the product quality and provide experimental basis for the process development and quality control of its preparation.