基于分析方法质量源于设计理念优化护肝片HPLC指纹图谱的研究
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摘要
目的:应用方法质量源于设计(AQb D)理念,建立护肝片HPLC指纹图谱方法并验证。方法:以峰个数(N)及五味子醇甲含量(SCH)、五味子酯甲量(StA)、五味子甲素量(SchA)和五味子乙素量(SchB)量为评价指标,采用Plackett-Burman设计在风险评估的基础上筛选出关键质量属性(CMAs)及关键质量参数(CMPs),然后对筛选出的显著项采用Box-Behnken设计得到CMAs及CMPs之间的响应模型。通过多变量回归分析得到最佳优化条件,并对最佳优化条件进行验证。结果:在风险评估的6个因子中筛选出了3个CMPs,分别为提取溶剂(A)、料液比(B)及色谱柱柱温(C),而筛选出有统计学意义的CMAs为N、五味子醇甲含量(SCH)及五味子甲素量(SchA)。通过响应面分析各因素与模型的变化趋势,得出其最佳优化条件为提取溶剂为79%甲醇,料液比为23 ml·g~(-1),柱温为32.2℃。在此条件下,验证试验测得N、SCH与SchA分别分别为20、0.628 0mg/片、0.133 0 mg/片,与模型预测值20.4、0.632 0 mg/片、0.138 0 mg/片接近。结论:所建立的方法可靠,为AQb D在中药分析领域的应用提供参考。
Objective: To establish and validate the identification of Hugan tablets by HPLC using the concept of analytical quality by design( AQb D). Methods: The number of peaks and the contents of schisandrin( SCH),schisantherin( St A),deoxyschizandrin( Sch A) and schisandrin B( Sch B) were taken as the analytical target profile( ATP),Plackett-Burman design( PBD) method was used to select critical method parameters( CMPs) and critical method attributes( CMAs) on the basis of risk assessment,and then the response model between CMAs and CMPs was established by Box-Behnken design( BBD). The optimal conditions were obtained via multivariable regression analysis and verified as well. Results: From the six factors of risk assessment,the extraction solvent( A),the column temperature( B) and the liquid to liquid ratio( C) were selected as CMPs. And CMAs were the number of peaks( N),and the contents of schisandrin( SCH) and deoxyschizandrin( SchA). The variation trends of each factor and model were analyzed by response surface analysis. The optimal conditions were as follows: the extraction solvent was 79% methanol,the column temperature was 32. 2℃ and the liquid to liquid ratio was 23 ml·g~(-1). Under the optimal conditions,N,SCH and Sch A respectively was 20,0. 628 0 mg/tablet and 0. 133 mg/tablet in the verification test,which was close to the predicted value of 20. 4,0. 632 0 mg/tablet and 0. 138 0 mg/tablet,respectively. Conclusion: The results proved that the method is reliable,which provide reference for the application of AQb D in the analysis of traditional Chinese medicine.
Objective: To establish and validate the identification of Hugan tablets by HPLC using the concept of analytical quality by design( AQb D). Methods: The number of peaks and the contents of schisandrin( SCH),schisantherin( St A),deoxyschizandrin( Sch A) and schisandrin B( Sch B) were taken as the analytical target profile( ATP),Plackett-Burman design( PBD) method was used to select critical method parameters( CMPs) and critical method attributes( CMAs) on the basis of risk assessment,and then the response model between CMAs and CMPs was established by Box-Behnken design( BBD). The optimal conditions were obtained via multivariable regression analysis and verified as well. Results: From the six factors of risk assessment,the extraction solvent( A),the column temperature( B) and the liquid to liquid ratio( C) were selected as CMPs. And CMAs were the number of peaks( N),and the contents of schisandrin( SCH) and deoxyschizandrin( SchA). The variation trends of each factor and model were analyzed by response surface analysis. The optimal conditions were as follows: the extraction solvent was 79% methanol,the column temperature was 32. 2℃ and the liquid to liquid ratio was 23 ml·g~(-1). Under the optimal conditions,N,SCH and Sch A respectively was 20,0. 628 0 mg/tablet and 0. 133 mg/tablet in the verification test,which was close to the predicted value of 20. 4,0. 632 0 mg/tablet and 0. 138 0 mg/tablet,respectively. Conclusion: The results proved that the method is reliable,which provide reference for the application of AQb D in the analysis of traditional Chinese medicine.
引文
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11 中国药典[S].2015年版.一部.961-962
12 唐秋竹,王艺纯,孟庆妍,等.HPLC法同时测定护肝片中五味子醇甲、五味子甲素、五味子乙素的含量[J].中国药品标准,2012,13(4):258-261
13 朱翔,韩立炜,马伟辰,等.护肝片中五味子含量测定方法的建立及不同厂家产品含量的比较[J].北京中医药大学学报,2011,34(4):258-262
14 Hassan EE,Pa rish RC,Gallo JM.Optimized formulation of magnetic chitosan microspheres containing the anticancer agent,ox antrazole[J].Pharm Res,1992,9(3):390-397
2 Pohl M,Smith K,Schweitzer M,et al.Implications and opportunities of applying Qb D principles to analytical measurements[J].Pharm Technol,2010,34(2):52,54,56-59
3 Musters J,van den Bos L,Kellenbach E.Applying Qb D principles to develop a generic UHPLC method which facilitates continual improvement and innovation throughout the product lifecycle for a commercial API[J].Org Process Res Dev,2013,17(1):87-96
4 崔雅华,王茜,徐冰,等.质量源于设计:基于知识组织的中药生产潜在关键工艺参数的辨识[J].中国试验方剂学杂志,2016,22(15):1-8
5 张小飞,邢传峰,果秋婷.基于质量源于设计(Qb D)理念优化穿心莲内酯固体脂质纳米粒[J].中草药,2015,46(2):194-200
6 罗赣,徐冰,孙飞,等.基于Qb D理念的微晶纤维素高速剪切湿法制粒过程试验研究[J].药学学报,2015,50(3):355-359
7 戴胜云,徐冰,张毅,等.质量源于设计(Qb D)在药物分析方法开发中的应用研究进展[J].药物分析杂志,2016,36(6):950-960
8 Kochling J,Wu W,Hua Y M,et al.A platform analytical quality by design(AQb D)approach for multiple UHPLCUV and UHPLC-MS methods development for protein analysis[J].J Pharm Biomed Anal,2016,125:130-139
9 杨家爱,曹天海.基于质量源于设计理念建立高效液相色谱方法[J].中国执业药师,2016,13(8):35-38
10 Yao H,Vancoillie J,D’Hondt M,et al.An analytical quality by design(AQb D)approach for a L-asparaginase activity method[J].J Pharm Biomed Anal,2016,117:232-239
11 中国药典[S].2015年版.一部.961-962
12 唐秋竹,王艺纯,孟庆妍,等.HPLC法同时测定护肝片中五味子醇甲、五味子甲素、五味子乙素的含量[J].中国药品标准,2012,13(4):258-261
13 朱翔,韩立炜,马伟辰,等.护肝片中五味子含量测定方法的建立及不同厂家产品含量的比较[J].北京中医药大学学报,2011,34(4):258-262
14 Hassan EE,Pa rish RC,Gallo JM.Optimized formulation of magnetic chitosan microspheres containing the anticancer agent,ox antrazole[J].Pharm Res,1992,9(3):390-397