目的 基于质量源于设计（QbD）理念以及满意度算法优化参麦注射液醇提水沉工艺。方法 使用危害及可操作性分析法对参麦注射液醇提水沉工艺进行风险评估，筛选出乙醇体积分数、提取时间、醇料比为醇提关键工艺参数，静置体系pH值、静置温度、静置时间为水沉关键工艺参数。采用Box-Behnken实验设计建立2个工艺环节的关键工艺参数和关键质量属性之间的多元线性回归模型，根据各质量属性的合格标准计算获得基于概率的麦冬醇提与混合水沉工艺的设计空间并进一步用基于满意度函数的多指标优化算法优化确定最佳操作条件。结果 对麦冬的醇提工艺而言，在设计空间范围内，乙醇体积分数89.0%、提取时间110 min，醇料比2.99时总体满意度最优，满意度为0.722。对混合水沉工艺而言，当物料pH值为4左右时，在2.0℃静置40 h时工艺的总体满意度最优，满意度为0.995；当物料pH值为5左右时，在2.0℃静置35 h时工艺的总体满意度最优，满意度为0.999。结论 基于QbD理念以及满意度算法确定的最佳条件有利于在保证产品质量的同时最大化降低生产成本，本研究对指导中药的制药工艺研究与工业化生产具有参考价值。

Objective The alcohol extraction and water precipitation processes of Shenmai Injection were optimized based on quality by design (QbD) concept and satisfaction algorithm. Methods Hazard and operational analysis method was applied to conduct risk assessment of various process parameters in alcohol extraction and water precipitation processes of Shenmai Injection. Ethanol concentration, extraction time and alcohol-material ratio were selected as the critical process parameters of alcohol extraction, and the material pH, temperature and time were selected as the critical process parameters of water precipitation. A multiple linear regression model of critical process parameters and critical quality attributes were established by using Box-Behnken design. A design space was delineated according to the level of each index. Finally, the optimum operating condition was determined by the multi-index optimization algorithm. Results Within the scope of the design space, when the alcohol concentration was 89.0%, the extraction time was 110 min, the alcohol-material ratio was 2.99, the desirability function of alcohol extraction of 0.722 was the best. When the material pH was about 4, the time was 40 h, the temperature was 2.0℃, the desirability function of water precipitation of 0.995 was the best. When the material pH was about 5, the time was 35 h, the temperature was 2.0℃, the desirability function of water precipitation of 0.999 was the best. Conclusion The optimal conditions were determined based on QbD and satisfaction algorithm were conducive to ensuring the product quality and reducing the cost of production. This study has reference value for the guidance of pharmaceutical process research and actual industrial production.

R283.6

国家"重大新药创制"科技重大专项（2018ZX09201011-002）