目的 基于质量源于设计理念优化了丹参川芎嗪注射液前处理过程中丹参浓缩膏的石硫工艺。方法 使用鱼刺图法对丹参浓缩膏石硫工艺涉及的各个参数进行了初步风险评估，筛选出了9个潜在关键工艺参数（critical process parameter，CPP），即石灰乳质量分数、加石灰乳速度、搅拌速度、加石灰乳后搅拌时间、硫酸质量分数、加酸速度、加酸后搅拌时间、静置时间和静置温度。采用Plackett-Burman（PB）实验设计法对9个潜在CPP进行进一步筛选，确定了石灰乳质量分数、加石灰乳后搅拌时间、加酸后搅拌时间和静置时间为石硫工艺的CPP。采用中心复合实验设计法建立CPP和关键质量属性之间的偏最小二乘回归模型，根据石硫上清液中各指标需要达到的水平，通过计算获得基于概率的设计空间。结果 推荐的石硫工艺操作空间为石灰乳质量分数12.0%～13.0%，加石灰乳后搅拌时间40～50 min，加酸后搅拌时间30～35 min，静置时间16～20 h。结论 在设计空间内进行操作有助于提高石硫工艺中间体质量一致性，本研究对实际工业生产具有一定参考价值。

Objective To optimize the lime milk-sulfuric acid process of Salviae Miltiorrhizae Radix et Rhizoma (SMRR) aqueous concentrate in the pretreatment of the manufacture of Danshen Chuanxiongqin Injection (DCI) based on the quality by design (QbD) concept. Methods Fishbone diagram method was applied to conduct preliminary risk assessment of various process parameters in lime milk-sulfuric acid process of SMRR aqueous extracts. Nine potential critical process parameters (CPP), including mass fraction of lime milk, flow rate of the lime milk addition, stirring speed, stirring time after lime milk addition, mass fraction of sulfuric acid, flow rate of the acid addition, stirring time after acid addition, standing time, and standing temperature, were identified. Plackett-Burman (PB) experiment design method was used to further screen the nine potential CPPs. As the result, the mass fraction of lime milk, stirring time after lime milk addition, stirring time after acid addition, and the standing time were filtered as CPPs of the lime milk-sulfuric acid process. A partial least squares regression models of critical process parameters and critical quality attributes were established using the central composite design and the design space methodology. Results The recommended operation space of the lime milk-sulfuric acid process in the pretreatment of the manufacture of DCI was as follow:mass fraction of lime milk of 12.0%-13.0%, stirring time after lime milk addition of 40-50 min, stirring time after acid addition of 30-35 min, and standing time of 16-20 h. Conclusion Operation in the design space is helpful to improve the consistency of lime milk-sulfuric acid process. This study is of valuable reference to actual industrial production.

R283.6

国家“重大新药创制”科技重大专项（2018ZX09201011-002）