基于QbD理念的三七总皂苷定量分析方法持续改进研究(1)
[摘要]该文提出基于质量源于设计(QbD)的中药分析方法持续改进策略。以三七总皂苷(PNS)5种皂苷类成分的超高效液相色谱(UPLC)定量分析方法开发为例，完成分析方法从HPLC到UPLC的转换。在UPLC开发中，采用PlackettBurman设计和BoxBehnken设计理解关键方法参数(CMP)与关键方法属性(CMA)之间的关系，建立贝叶斯概率设计空间；优选稳健色谱条件为初始乙腈20%，等度时间10 min，梯度变化速率6 %·min-1，分析时间17 min，采用Accuracy profile进行方法学验证。在相同的分析目标(ATP)下，从色谱条件、CMP辨识结果、CMPCMA关系模型、系统适用性等方面对PNS 的HPLC和UPLC定量分析性能的一致性进行比较，结果表明UPLC可缩短分析时间、提高关键峰对分离度、色谱系统适用性满足要求，UPLC可替代HPLC进行PNS定量分析。
[关键词]质量源于设计； UPLC； 持续改进； 贝叶斯设计空间； 三七总皂苷
, http://www.100md.com
[Abstract]This study is aimed to propose a continual improvement strategy based on quality by design (QbD) An ultra high performance liquid chromatography (UPLC) method was developed to accomplish the method transformation from HPLC to UPLC of Panax notogineng saponins (PNS) and achieve the continual improvement of PNS based on QbD， for example PlackettBurman screening design and BoxBehnken optimization design were employed to further understand the relationship between the critical method parameters (CMPs) and critical method attributes (CMAs) And then the Bayesian design space was built The separation degree of the critical peaks (ginsenoside Rg1 and ginsenoside Re) was over 20 and the analysis time was less than 17 min by a method chosen from the design space with 20% of the initial concentration of the acetonitrile， 10 min of the isocratic time and 6%·min-1 of the gradient slope At last， the optimum method was validated by accuracy profile Based on the same analytical target profile (ATP)， the comparison of HPLC and UPLC including chromatograph method， CMA identification， CMPCMA model and system suitability test (SST) indicated that the UPLC method could shorten the analysis time， improve the critical separation and satisfy the requirement of the SST In all， HPLC method could be replaced by UPLC for the quantity analysis of PNS
, 百拇医药
[Key words]quality by design； UPLC； continual improvement； bayesian design space； Panax notogineng saponins
三七Panax notoginseng(Burk)FHChen為五加科植物，具有散瘀止血、消肿止痛之功效[1]。三七总皂苷(Panax notogineng saponins，PNS)为三七主根或根茎经加工制成的总皂苷提取物，已收录在《中国药典》2015 年版一部[2]。药典中PNS 5种皂苷类成分的含量测定采用HPLC，乙腈水梯度洗脱，流速15 mL·min-1。该法分析时间长，流速大、流动相消耗大，系统背压偏高，峰型也不尽理想。笔者曾尝试采用质量源于设计(quality by design，QbD)方法提高PNS分析方法性能。第1次方法改进时采用色谱柱(46 mm×150 mm，5 μm)，将流速降低到1 mL·min-1，但分析时间没有变化[3]。第2次方法改进选择色谱柱(46 mm × 75 mm，25 μm)，流速为08 mL·min-1，分析时间缩减到36 min，关键分离度为160，基本达到色谱分离的要求[4]。
, http://www.100md.com
超高效液相色谱(ultra high performance liquid chromatography，UPLC)具有高效、灵敏、快速的优点。本次研究中以三七总皂苷UPLC开发为例，完成分析方法从HPLC到UPLC的转换，期望缩短分析时间，减少有机溶剂消耗，并实现PNS分析方法的持续改进。在PNS的UPLC开发中，首先定义分析目标(analytical target profile，ATP)，然后采用风险评估(risk evaluation)辨识关键方法属性(critical method attributes，CMAs)和键方法参数(critical method parameters，CMPs)，采用回归模型建立CMAs和CMPs关系模型，基于模型开发分析方法设计空间(design space，DSp)，最后基于DSp优化分析条件。方法开发完成后，以CMPsCMAs关系模型的准确性和系统适用性是否改变为判断标准，为评价分析方法改进的有效性，为新分析方法的应用提供参考。, 百拇医药(戴胜云 徐冰 史新元 徐翔 孙英强 乔延江)
[关键词]质量源于设计； UPLC； 持续改进； 贝叶斯设计空间； 三七总皂苷
, http://www.100md.com
[Abstract]This study is aimed to propose a continual improvement strategy based on quality by design (QbD) An ultra high performance liquid chromatography (UPLC) method was developed to accomplish the method transformation from HPLC to UPLC of Panax notogineng saponins (PNS) and achieve the continual improvement of PNS based on QbD， for example PlackettBurman screening design and BoxBehnken optimization design were employed to further understand the relationship between the critical method parameters (CMPs) and critical method attributes (CMAs) And then the Bayesian design space was built The separation degree of the critical peaks (ginsenoside Rg1 and ginsenoside Re) was over 20 and the analysis time was less than 17 min by a method chosen from the design space with 20% of the initial concentration of the acetonitrile， 10 min of the isocratic time and 6%·min-1 of the gradient slope At last， the optimum method was validated by accuracy profile Based on the same analytical target profile (ATP)， the comparison of HPLC and UPLC including chromatograph method， CMA identification， CMPCMA model and system suitability test (SST) indicated that the UPLC method could shorten the analysis time， improve the critical separation and satisfy the requirement of the SST In all， HPLC method could be replaced by UPLC for the quantity analysis of PNS
, 百拇医药
[Key words]quality by design； UPLC； continual improvement； bayesian design space； Panax notogineng saponins
三七Panax notoginseng(Burk)FHChen為五加科植物，具有散瘀止血、消肿止痛之功效[1]。三七总皂苷(Panax notogineng saponins，PNS)为三七主根或根茎经加工制成的总皂苷提取物，已收录在《中国药典》2015 年版一部[2]。药典中PNS 5种皂苷类成分的含量测定采用HPLC，乙腈水梯度洗脱，流速15 mL·min-1。该法分析时间长，流速大、流动相消耗大，系统背压偏高，峰型也不尽理想。笔者曾尝试采用质量源于设计(quality by design，QbD)方法提高PNS分析方法性能。第1次方法改进时采用色谱柱(46 mm×150 mm，5 μm)，将流速降低到1 mL·min-1，但分析时间没有变化[3]。第2次方法改进选择色谱柱(46 mm × 75 mm，25 μm)，流速为08 mL·min-1，分析时间缩减到36 min，关键分离度为160，基本达到色谱分离的要求[4]。
, http://www.100md.com
超高效液相色谱(ultra high performance liquid chromatography，UPLC)具有高效、灵敏、快速的优点。本次研究中以三七总皂苷UPLC开发为例，完成分析方法从HPLC到UPLC的转换，期望缩短分析时间，减少有机溶剂消耗，并实现PNS分析方法的持续改进。在PNS的UPLC开发中，首先定义分析目标(analytical target profile，ATP)，然后采用风险评估(risk evaluation)辨识关键方法属性(critical method attributes，CMAs)和键方法参数(critical method parameters，CMPs)，采用回归模型建立CMAs和CMPs关系模型，基于模型开发分析方法设计空间(design space，DSp)，最后基于DSp优化分析条件。方法开发完成后，以CMPsCMAs关系模型的准确性和系统适用性是否改变为判断标准，为评价分析方法改进的有效性，为新分析方法的应用提供参考。, 百拇医药(戴胜云 徐冰 史新元 徐翔 孙英强 乔延江)