Li Yao-Yao, Zhang Kai-Xuan, Xiong Hao-Shu, Zhao Wan-Shun, Han Ming-Yue, Yan Kai-Jing, Zhang Shun-Nan
National & Local United Engineering Laboratory for TCM Advanced Manufacturing Technology,Tasly Pharmaceutical Group Co.,Ltd. Tianjin 300410,China China Pharmaceutical University Nanjing 211198,China.
National & Local United Engineering Laboratory for TCM Advanced Manufacturing Technology,Tasly Pharmaceutical Group Co.,Ltd. Tianjin 300410,China.
Zhongguo Zhong Yao Za Zhi. 2021 Jun;46(11):2816-2823. doi: 10.19540/j.cnki.cjcmm.20210125.301.
The mixing process is one of the key operation units for solid preparation of traditional Chinese medicine. The physical properties such as particle size, density and viscosity of the mixture are key factors that need to be controlled, which will directly affect the performance of the preparation molding process and product quality. Subsequent dripping process performance and appearance qua-lity of dripping pills will be affected by dynamic viscosity of materials in the mixing process. Based on this, with mixing process of compound Danshen dripping pills as the object, a feedforward control method for the dripping pill mixing process was established based on the concept of quality by design(QbD). Firstly, critical quality attribute(CQA)-dynamic viscosity, critical material attributes(CMAs)-the moisture content of compound Danshen extract, average molecular weight of polyethylene glycol 6000 and critical process parameter(CPP)-mixing temperature were identified through the analysis of properties for multiple batches of the raw materials and excipients as well as technological mechanism. Then the Box-Behnken experimental design was used to establish the regression model among CMA, CPP and CMA(R■=0.972 0, RMSE =16.24) to obtain the design space. Finally, through the verification of three batches within the design space, the mixing process temperature was adjusted according to the properties of the raw materials and exci-pients to achieve accurate control of the dynamic viscosity attribute. The relative deviation between the actual dynamic viscosity value and the target value was less than 3.0 %. The feedforward control of the mixing process of compound Danshen dripping pills was rea-lized in this study, which can contribute to improving quality consistency of the mixing process intermediates, simultaneously provide a reference for the research on the process quality control of other Chinese medicine dripping pills.
混合过程是中药固体制剂的关键操作单元之一。混合物的粒度、密度和粘度等物理性质是需要控制的关键因素，这些因素将直接影响制剂成型过程的性能和产品质量。混合过程中物料的动态粘度会影响后续滴丸的滴制过程性能和滴丸外观质量。基于此，以复方丹参滴丸混合过程为对象，基于质量源于设计（QbD）理念建立了滴丸混合过程的前馈控制方法。首先，通过对多批次原料和辅料的性质以及工艺机理分析，确定了关键质量属性（CQA）——动态粘度、关键物料属性（CMA）——复方丹参提取物含水量、聚乙二醇6000平均分子量和关键工艺参数（CPP）——混合温度。然后采用Box-Behnken实验设计建立CMA、CPP和CQA之间的回归模型（R■=0.972 0，RMSE =16.24）以获得设计空间。最后，通过对设计空间内三批次的验证，根据原料和辅料的性质调整混合过程温度，实现对动态粘度属性的精确控制。实际动态粘度值与目标值的相对偏差小于3.0%。本研究实现了复方丹参滴丸混合过程的前馈控制，有助于提高混合过程中间体的质量一致性，同时为其他中药滴丸的过程质量控制研究提供参考。
