目的 基于质量源于设计（quality by design，QbD）理念，结合蒙特卡洛抽样法，构建小儿消食颗粒（Xiaoer Xiaoshi Granules，XXG）提取工艺最优参数。方法 采用鱼骨图对XXG提取工艺的关键工艺参数（critical process parameters，CPPs）进行筛选，通过正交试验探究CPPs对关键质量属性（critical quality attributes，CQAs）的影响，进一步，采用Box-Behnken设计试验对提取工艺持续优化并验证，根据试验结果，结合蒙特卡洛抽样法，建立稳健设计空间，并构建成本函数，计算得到其在稳健设计空间范围内的最佳提取工艺参数。结果 确定CPPs为第1次加水倍量、第2次加水倍量和提取时间；CQAs为总固体提取量、总黄酮提取量；XXG提取工艺稳健设计空间参数范围为第1次提取水倍量10.8～14.0倍，第2次提取水倍量10.8～14.0倍，提取时间72.0～81.4 min；依据成本函数计算得到的最佳提取工艺为第1次提取水倍量13.9倍，第2次提取水倍量11.9倍，提取时间81.4 min，总固体提取率为230.1 mg/g，总黄酮提取率为5.1 mg/g，与正交试验优化得到的提取方法比较，提取成本降低了11.82%。结论 基于QbD理念和蒙特卡洛抽样法优化得到的XXG提取工艺参数具有可行性，且提取成本经过持续优化后有所降低，为中药制剂工艺开发参数精确化，工艺高效化研究提供参考价值。

Objective To optimize the extraction process parameters for Xiaoer Xiaoshi Granules (小儿消食颗粒，XXG) by applying the quality by design (QbD) concept, enhanced with Monte Carlo sampling methods. Methods A fishbone diagram was utilized to identify the critical process parameters (CPPs) for the XXG extraction. The effects of these CPPs on the critical quality attributes (CQAs) were assessed through orthogonal experiment. The extraction process was further optimized and validated using a Box-Behnken design. A robust design space was defined via Monte Carlo simulations, and cost function was developed to determine the optimal parameters within this space. Results The determined CPPs were the first and second extraction water quantity and the extraction time; CQAs were the total solids extraction and total flavonoids extraction. The robust design parameters were set as follows: the first extraction water quantity: 10.8—14.0 times, the second extraction water quantity: 10.8—14.0 times, and the extraction time: 72.0—81.4 min. The optimal extraction process calculated according to the cost function was: first extraction water quantity of 13.9 times, second extraction water quantity of 11.9 times, and extraction time of 81.4 min. The total solid extraction rate was 230.1 mg/g, and the total flavonoid extraction rate was 5.1 mg/g. Compared to the method optimized by orthogonal experiments, the optimized process reduced extraction costs by 11.82%. Conclusion The optimized extraction parameters for XXG, using the QbD concept and Monte Carlo methods, proved feasible and cost-effective. This optimization provides a reference for precise and efficient process development in traditional Chinese medicine formulations.

R283.6

国家重点研发计划项目（2023YFC3504505）；国家重点研发计划项目（2022YFC3501902）；国家自然科学基金项目（82274110）；国家医学攻关产教融合创新平台——中药智能制造工程平台项目（90010062820031）