目的 优化羌芩颗粒的干法制粒成型工艺，并对颗粒进行质量控制。方法 以颗粒成型率、吸湿率（H）、溶化率和休止角（α）的综合评分为指标，采用Box-Behnken设计-响应面法结合AHP-CRITIC混合加权法建立干法制粒关键工艺参数（critical process parameters，CPPs）和关键质量属性（critical quality attributes，CQAs）的数学模型，通过该模型构建干法制粒的设计空间，并进行蒙特卡洛验证。采用单形格子设计对满足制粒工艺的甘露醇、麦芽糊精、糊精进行辅料配比筛选，确定最佳辅料配比并进行验证。采用粉体学评价方法对羌芩颗粒各项物理质量属性指标进行综合表征，建立由松装密度（D_a）、振实密度（D_c）、α、豪斯纳比（IH）、H、含水量（HR）、颗粒间孔隙率（I_e）、卡尔指数（IC）、比表面积（SSA）、粒径＜50 µm百分比（Pf）、分布宽度（span）、分布范围（width）、均匀性（HG）共13个二级物理质量指标构成的颗粒物理指纹图谱，评价不同批次间颗粒质量的一致性。结果 羌芩颗粒干法制粒CPPs的设计空间为送料频率37～45 Hz，滚轮频率8.0～11.8 Hz，滚轮压力40～50 kg/cm²。最佳辅料配比为甘露醇86%，糊精14%。15批样品物理指纹图谱的相似度均大于0.95。结论 优选后的羌芩颗粒干法制粒成型工艺稳定可行，中间体物理性质质量评价科学合理，可为中药新药的开发及工业化放大生产提供参考。

Objective To optimize the dry granulation and forming process of Qiangqin Granules (QG, 羌芩颗粒) and control the quality of the granules. Methods The mathematical models of critical process parameters (CPPs) and critical quality attributes (CQAs) of dry granulation were established by Box-Behnken design-response surface method combined with AHP-CRITIC hybrid weighting method using the combined scores of granule forming rate, moisture absorption rate (H), dissolution rate and angle of repose (α) as indicators, and the design space of dry granulation was constructed by this model and validated by Monte Carlo. Simplex-lattice design was used to screen the excipient ratios of mannitol, maltodextrin and dextrin that satisfied the granulation process, and the best excipient ratios were determined and validated. The physical quality property indexes of QG were comprehensively characterized by the powderological evaluation method, and the physical fingerprint of the granules consisting of 13 secondary physical quality indexes, including bulk density (D_a), tap density (D_c), α, Hausner ratio (IH), H, water content (HR), interparticle porosity (I_e), Karl index (IC), specific surface area (SSA), particle size < 50 µm percent (Pf), span, width and homogeneity (HG), was established to evaluate the consistency of granule quality among different batches. Results The design space of dry granulation CPPs of QG was 37 − 45 Hz for feeding frequency, 8.0 − 11.8 Hz for roller frequency, and 40 − 50 kg/cm² for roller pressure. 86% of mannitol and 14% of dextrin were used as the optimal excipient ratios. The similarity of the physical fingerprint profiles of 15 batches of samples was greater than 0.95. Conclusion The optimized dry granulation and forming process of QG are stable and feasible, the physical property quality evaluation of the intermediates is scientific and reasonable, which can provide reference for the development and industrial scale up production of new Chinese medicines.

连云港市重大技术攻关“揭榜挂帅”项目：中药口服固体制剂智能化连续制造关键技术研究（CGJBGS2101）