基于质量源于设计理念优化都梁方渗漉提取工艺

Optimization of percolation extraction process of Duliang formula based on quality by design concept

目的基于质量源于设计(quality by design,QbD)理念,优化经典组方都梁方的渗漉提取工艺。方法采用鱼骨图结合失效模式与效应分析(failure mode effects analysis,FMEA)确定乙醇体积分数、乙醇用量、渗漉体积流量、浸渍时间为关键工艺参数(critical process parameters,CPPs);基于质量标志物(quality markers,Q-Marker)“五原则”确定欧前胡素、异欧前胡素、佛手柑内酯、阿魏酸、Z-藁本内酯、洋川芎内酯A含量及干膏率为关键质量属性(critical quality attributes,CQAs),采用HPLC法测定6个指标成分的含量;应用层次分析(analytic hierarchy process,AHP)-基于指标相关性的权重确定方法(criteria importance through intercriteria correlation,CRITIC)混合加权法确定6个成分和干膏率的权重系数,进行综合评分;通过Box-Behnken设计建立CQAs和CPPs之间的数学模型,构建都梁方渗漉提取工艺的设计空间并进行工艺验证。结果方差分析结果显示,2次项回归模型的方差显著(P<0.01),且失拟值不显著,表明所建模型具有统计学意义;渗漉提取工艺为乙醇体积分数50%~55%、乙醇用量为8~10倍、渗漉体积流量为3~4 mL/min、浸渍时间为12~24 h。结论基于QbD理念优化的都梁方渗漉提取工艺合理、可行且稳定可靠,为其制剂开发的工艺研究及质量控制提供实验基础。

Objective Based on the idea of quality by design(QbD),the percolation extraction process of the classic formula Duliang formula was optimized.Methods The fishbone diagram combined with failure mode effects analysis was used to determine the ethanol concentration,ethanol dosage,percolation rate and soaking time as the critical process parameters(CPPs).Based on the"five principles"of quality markers(Q-Marker),the contents of imperatorin,isoimperatorin,bergapten,ferulic acid,Z-ligustilide,senkyunolide A and dry paste rate were determined as critical quality attributes(CQAs).The contents of six index components were determined by HPLC.The weight coefficients of six components and dry paste rate were determined by using analytic hierarchy process mixed with criteria importance through intercriteria correlation for comprehensive scoring.The mathematical model between CQAs and CPPs was established by Box-Behnken design,and the design space of percolation extraction process of Duliang formula was constructed and the process was verified.Results The results of variance analysis showed that the variance of the quadratic regression model was significant(P<0.01),and the misfit value was not significant,indicating that the model was statistically significant.The optimized percolation extraction process for Duliang formula is as follows:ethanol concentration 50%—55%,ethanol dosage 8—10 times,percolation speed 3—4 mL/min,impregnation time 12—24 h.Conclusion The percolation extraction process of Duliang formula based on the idea of QbD is reasonable,feasible,stable and reliable,which provides experimental basis for the technological research and quality control of its preparation development.