蒋建兰 ^{1, 2}，单潇潇 ^{1, 2}，孙 露 ^{1, 2}，张凯旋^{1, 2}
AuthorsHTML:蒋建兰 ^{1, 2}，单潇潇 ^{1, 2}，孙 露 ^{1, 2}，张凯旋^{1, 2}
AuthorsListE:Jiang Jianlan ^{1, 2}，Shan Xiaoxiao ^{1, 2}，Sun Lu ^{1, 2}，Zhang Kaixuan ^{1, 2}
AuthorsHTMLE:Jiang Jianlan ^{1, 2}，Shan Xiaoxiao ^{1, 2}，Sun Lu ^{1, 2}，Zhang Kaixuan ^{1, 2}
Unit:1. 天津大学系统生物工程教育部重点实验室，天津300350；
2. 天津大学化工学院，天津 300350
Unit_EngLish:1. Key Laboratory of Systems Bioengineering of Ministry of Education，Tianjin University，Tianjin 300350，China；
2. School of Chemical Engineering and Technology，Tianjin University，Tianjin 300350，China
Abstract_Chinese:将质量源于设计(QbD)理念应用于苦参生物碱的纯化工艺，建立稳定可控的操作空间．以苦参总生物碱(TASF)、苦参碱(MT)和氧化苦参碱(OMT)的解吸量为工艺评价指标，静态吸附和解吸试验选取性能最优的大孔树脂作为纯化过程中的吸附剂，单因素和多因素显著性试验(PBD)筛选并确定关键工艺参数(CPPs)，中心点复合试验(CCD)进一步优化工艺参数，建立工艺参数和工艺评价指标之间的数学模型，以此获得操作空间，在空间内、外选点，对模型及设计空间进行验证．NK-109型大孔树脂吸附性能良好，为该试验的最优树脂．上样液pH值、洗脱剂乙醇浓度和洗脱流速为该试验的显著性影响因素．关键工艺参数与工艺评价指标之间回归方程的P值均小于0.05，而失拟项均大于0.05，表明回归方程显著．在苦参总生物碱解吸量 0.87mg/g，苦参碱解吸量 32.50μg/g，氧化苦参碱解吸量 244.10μg/g的工艺指标下，设计空间为：洗脱流速 25.0mL/h，洗脱剂乙醇体积分数82.0%～87.0%，上样液pH值5.3～6.2．验证结果表明模型的预测能力良好，空间内的点满足工艺指标，而空间外的点无法达到生产要求，设计空间稳定．质量源于设计理念的引用可以为中药的分离纯化过程提供稳定可控的操作空间，在确定工艺指标的基础上，灵活设置工艺参数，保证产品质量可控．
Abstract_English:The quality by design(QbD)concept was applied to the purification process of alkaloids in Sophora flaves-cens to establish a stable and controllable operation space. The matrine(MT)，oxymatrine(OMT)，and total alkaloid contents of S. flavescens(TASF)were used as indicators. Static adsorption and desorption tests were conducted to screen the macroporous resin for the best adsorbent in the purification process. Critical process parameters(CPPs) were selected and determined using the Plackeet-Burmann design(PBD) and single-factor experiments. To obtain a design space，central composite designed(CCD) experiments were used to optimize the process parameters and establish a mathematical model between critical process parameters and critical quality attributes. To verify the model and design space，a point was selected in and out of the design space. Results show that NK-109resin showed good adsorption properties and was the most suitable resin in this test. The pH of the load solution，the eluent concentration，and the elution rate were critical process parameters. The regression equations between critical process parameters and process critical quality attributes had P＜0.05，and the misfit terms had P＞0.05，indicating that the regression equations were significant. When TASF 0.87mg/g，MT 32.50μg/g，and OMT 244.10μg/g，the recommended operating space was as follows：elution rate of 25.0mL/h，pH 5.3—6.2in the load solution，and eluent volume fraction of 82.0%—87.0%. The verification results revealed that the model had good predictive power，points in the space could meet the process indicators，and points outside the space could not meet the production requirements，indicating that the design space was stable. The QbD concept can provide a stable and controllable operation space for the separation and purification of traditional Chinese medicine. Based on the determination of process indicators，the flexibility of process parameters can be increased to ensure controllable product quality.
Keyword_Chinese:质量源于设计；苦参；纯化过程；优化
Keywords_English:quality by design；Sophora flavescens；purification process；optimization

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