目的 基于分析质量源于设计（analytical quality by design，AQbD）理念，同时开发检测盐酸青藤碱制药过程3种物料的指纹图谱分析方法。方法 采用实验设计优化方法参数，通过哑元（dummy variables，虚拟变量）表征物料类型，将物料类型纳入AQbD过程。建立定量模型，建立方法可操作设计区域（method operable design region，MODR）并进行验证，考察方法的耐用性及方法学，应用于多批次物料进行相似度评价。结果 建立了关键方法参数（critical method parameters，CMPs）、物料类型（material type，MT）与关键质量属性（critical quality attributes，CQAs）之间的定量模型，模型的P值 均＜0.000 1，R²均大于0.80。优化获得了MODR并成功进行验证，通过了方法学考察，相对保留时间RSD＜0.40%，相对峰面积RSD＜5.0%。除YC10批次药材、JH3批次碱化液之外，其余物料与对照图谱的相似度大于0.95。所建立方法适用于盐酸青藤碱生产过程所涉及的药材、渗漉液、碱化液3种物料的指纹图谱相似度评价。结论 所建立的HPLC指纹图谱方法适用于检测3种盐酸青藤碱制药过程物料。建立分析方法的流程有望推广用于中药制药工业系列相关物料检测方法开发。

Objective Based on the concept of analysis quality by design (AQbD), to simultaneously develop fingerprint analysis methods for three materials in the pharmaceutical process of sinomenine hydrochloride. Methods Design of experiment was used to optimize method parameters. Dummy variables were used to represent material types, and the material type was included in the AQbD process. A quantitative model was established, and the method operating design region (MODR) was established and validated to investigate the robustness and methodology of the method, which was applied to evaluate the similarity of multiple batches of materials. Results A quantitative model was established between critical method parameters (CMPs), material type (MT), and critical quality attributes (CQAs), with all model P values being less than 0.000 1 and R² values greater than 0.80. The MODR was optimized and successfully validated. The methodology was investigated with relative retention time RSD < 0.40% and relative peak area RSD generally < 5.0%. Except for batch YC10 of medicinal material and batch JH3 of alkalized liquid, the similarity value to the reference fingerprint was greater than 0.95 for all other materials. The established method is suitable for the similarity evaluation of fingerprint of three materials involved in the production process of sinomenine hydrochloride, including medicinal materials, percolation solutions, and alkalized solutions. Conclusion The HPLC fingerprint method established in this study is suitable for the analysis of three materials in the sinomenine hydrochloride pharmaceutical process. The process of establishing the analytical method in this study is expected to be promoted for the development of detection methods for related materials in the traditional Chinese medicine pharmaceutical industry.

R283.6

湖南省自然科学基金资助项目（2022JJ80084）;国家中医药管理局创新团队与人才支持计划（ZYYCXTD-D-202002）