基于质量源于设计的复方丹参滴丸混合工艺前馈控制方法研究

Research on feedforward control method of mixing process for compound Danshen Dripping Pills based on quality by design(QbD)

混合工艺是中药固体制剂的关键操作单元之一,混合物料的粒度、密度、黏度等物理属性会直接影响制剂成型工艺性能,进而影响到产品质量,是需要进行控制的关键因素。滴丸剂混合工艺中物料的动力黏度会影响后续滴制工艺性能,进而影响滴丸产品的质量。该文以复方丹参滴丸混合工艺为对象,基于质量源于设计(quality by design,QbD)理念,建立了一种基于原辅料属性的滴丸混合工艺前馈控制方法。首先,通过多批次原辅料属性数据相关分析和工艺机制分析,识别出了关键质量属性(critical quality attribute,CQA)-动力黏度,以及对CQA产生显著影响的关键物料属性(critical material attribute,CMA)-原料复方丹参提取物含水量、辅料聚乙二醇6000平均相对分子质量,以及关键工艺参数(critical process parameter,CPP)-混合工艺温度;随后采用Box-Behnken试验设计,建立CMA、CPP与CMA之间的回归模型(R_(Pred)^(2)=0.9720,RMSE=16.24),得到设计空间;最后,在设计空间范围内经3批次验证,基于混合中间体动力黏度目标值,可针对原辅料性质相应调整混合工艺温度,动力黏度实际值与目标值的相对偏差低于3.0%,能够达到对动力黏度属性的精准控制。该研究实现了对复方丹参滴丸混合工艺过程的前馈控制,有助于提高混合工艺中间体质量一致性,也为其他中药滴丸产品工艺过程质量控制研究提供参考。

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_(Pred)^(2)=0.9720,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.