设计空间法优化银杏叶滴丸滴制工艺

申基琛+王青青+陈安+潘方来+龚行楚+瞿海斌

[摘要] 运用设计空间法优化银杏叶滴丸滴制工艺。首先通过预实验和文献调研确定潜在关键工艺参数和潜在关键工艺评价指标，然后采用Box-Behnken设计开展试验，根据试验结果确定关键工艺参数和关键工艺评价指标，再采用二阶多项式模型描述关键工艺参数与关键工艺评价指标间的定量关系，最后计算获得基于概率的设计空间并验证。验证结果表明，在工艺参数设计空间内操作能够确保银杏叶滴丸高效产出。银杏叶滴丸滴制工艺关键参数的推荐操作范围为：滴距5.5～6.7 cm，滴速59～60 滴/min，为银杏叶滴丸的工业生产提供了参考。

[关键词] 银杏叶滴丸；滴制工艺；关键工艺参数；设计空间

[Abstract] In this paper， a design space approach was applied to optimize the dropping process of Ginkgo biloba dropping pills. Firstly， potential critical process parameters and potential process critical quality attributes were determined through literature research and pre-experiments. Secondly， experiments were carried out according to Box-Behnken design. Then the critical process parameters and critical quality attributes were determined based on the experimental results. Thirdly， second-order polynomial models were used to describe the quantitative relationships between critical process parameters and critical quality attributes. Finally， a probability-based design space was calculated and verified. The verification results showed that efficient production of Ginkgo biloba dropping pills can be guaranteed by operating within the design space parameters. The recommended operation ranges for the critical dropping process parameters of Ginkgo biloba dropping pills were as follows： dropping distance of 5.5-6.7 cm， and dropping speed of 59-60 drops per minute， providing a reference for industrial production of Ginkgo biloba dropping pills.

[Key words] Ginkgo biloba dropping pills；dropping process；critical process parameters；design space

銀杏叶具有活血化瘀、平喘敛肺、清心明智等功效，其制剂在临床上常用于治疗冠心病、心绞痛、脑梗死、老年痴呆等疾病[1]。银杏叶滴丸是《中国药典》2015年版一部[2]里的收载品种，其制法为：取银杏叶提取物，加聚乙二醇，加热熔化，混匀，滴入甲基硅油冷却剂中，制成丸。从工业生产实际情况分析，滴制工艺对滴丸的质量和产量影响较大。滴制工艺参数较多，如滴速、滴头与冷凝液液面距离、冷凝液温度等。但是，目前针对银杏叶滴丸滴制工艺的研究很少，滴制工艺参数与滴丸质量和产量的关系并不明确。

近年来，质量源于设计（quality by design，QbD）理念在国际制药领域产品和工艺开发中得到大力推行[3]。QbD强调理解药品生产过程，即明确工艺参数如何影响工艺指标。……