目的 采用统计过程控制方法建立热毒宁注射液栀子中间体纯化工艺过程批放行标准,保证批间质量的均一性和稳定性。方法 收集48批栀子中间体纯化溶液作为训练集样本,测定绿原酸、山栀苷、京尼平苷酸、去乙酰车叶草酸甲酯、京尼平龙胆双糖苷、栀子苷和总酸的量;建立定量放行标准,扫描样本近红外光谱(NIRS),建立基于光谱信息的定性放行标准。应用Box-Behnken实验设计制备不同工艺条件下的17批栀子中间体纯化溶液作为验证集,验证建立的定量标准和定性标准的可行性。结果 建立的定量放行范围为绿原酸5.753～6.713 mg/g、山栀苷9.456～10.723 mg/g、京尼平苷酸3.313～4.401 mg/g、去乙酰车叶草酸甲酯15.260～16.419 mg/g、京尼平龙胆双糖苷30.529～33.473 mg/g、栀子苷165.17～175.16 mg/g和总酸45.028～53.118 mg/g;建立的NIRS定性放行限为Hotelling T²=4.067 8,DModX=1.218 8。验证集中只有第1、5、7、9、10、14、15、16、17批的样本各成分的量均在定量放行控制限范围内,NIRS信息也在定性放行控制限范围内。结论 运用NIRS和统计过程控制技术相结合,建立批放行定量和定性标准,简单可行,可用于栀子中间体纯化工艺过程质量控制。

Objective To establish the batch release criteria of Gardenia jasminoides intermediate purification process based on statistical process control technology in order to ensure the batch-to-batch consistency and stability. Methods Forty-eight batches of G. jasminoides intermediate purified solution were collected as the calibration set. The content of chlorogenic acid, shanzhiside, geniposidic acid, deacetyl asperulosidic acid methyl ester, genipin-1-β-D-gentiobioside, geniposide, and total acid were determined to establish the quantitative release criteria. Near-infrared spectra (NIRS) were acquired to establish the qualitative release criteria. Seventeen batches of G. jasminoides intermediate purified solution were prepared under different process conditions by the Box-Behnken experimental design. They were regarded as the validation set to verify the feasibility of the established quantitative and qualitative release criteria. Results The established quantitative release ranges were: chlorogenic acid 5.753—6.713 mg/g,shanzhiside 9.456—10.723 mg/g, geniposidic acid 3.313—4.401 mg/g, deacetyl asperulosidic acid methyl ester 15.260—16.419 mg/g, genipin-1-β-D-gentiobioside 30.529—33.473 mg/g, geniposide 165.17—175.16 mg/g, and total acid 45.028—53.118 mg/g, respectively. The established qualitative release upper limits were: Hotelling T² = 4.067 8 and DModX = 1.218 8. For sample 1, 5, 7, 9, 10, 14—17 from the validation set, the content of quality control indicators satisfied the quantitative release criteria and NIRS satisfied the qualitative release criteria. Conclusion Based on NIRS and statistical process control technology, the developed quantitative and qualitative release criteria are simple and feasible. They could be used for the production quality control of G. jasminoides intermediate purification process.

科技部重大新药创制:现代中药创新集群与数字制药技术平台(2013ZX09402203)