质量源于设计在银杏叶片制粒工艺中的应用(Ⅳ):原料质量波动的影响及控制

Application of quality by design in granulation process for ginkgo leaf tablet(Ⅳ):influence and control of raw materials' quality variation

原料质量变异影响产品质量一致性和临床疗效。该文以银杏叶片高速剪切湿法制粒工艺(HSWG)为研究对象,收集不同厂家和批次的银杏叶提取物和辅料微晶纤维素,模拟原料波动。实时记录湿法制粒过程扭矩,分析湿软材黏着力。结合物理指纹图谱,考察原料粉末物理质量变异对颗粒中间体粉体学性质的影响。根据湿法制粒Regime map理论,通过无量纲参数计算,判断银杏叶片HSWG中颗粒的润湿与成核处于机械分散区,颗粒收率和颗粒粒径分布曲线表明该区域过程输出的不稳定性。采用正交偏最小二乘(OPLS)法建立18批原料粉末粉体学性质和和银杏叶颗粒中值粒径(D_(50))的关联模型,以变量投影重要性(VIP)筛选原料关键物料属性(CMAs)。结果表明原料粉末吸湿性、休止角、豪斯纳比、卡尔指数、D_(10)、干燥失重影响颗粒粒度。进一步将银杏叶颗粒压制成片,并测定片剂抗张强度,发现原料质量波动未导致片剂机械强度的降低,银杏叶颗粒关键质量属性设计空间和过程设计空间稳健可靠,可有效应对原料质量波动。

Raw materials＇ quality variation could affect the quality consistency of product and the clinical efficacy. In this paper, the high shear wet granulation （HSWG） process of the ginkgo leaf tablet was taken as the research object. Ginkgo biloba extracts and excipients microcrystalline cellulose collected from various sources and batches were used to simulate raw materials＇ quality variation. Real-time torque was recorded to analyze the viscosity of the wetting mass, and then by combining with physical fingerprint, the impact of physical quality variation of powders on granule properties could be investigated. Based on regime map thesis, whether the granules＇ nucleation mode was in mechanical dispersion regime was determined by calculating dimensionless parameters, which would lead to the unstable output in considerations of granule yield ratio and particle size distribution （PSD） curve. The orthogonal partial least square （OPLS） model was adopted to build the relationship between the micromeritic properties and the mediangranule size （D50） of Ginkgo biloba granules and then the critical material attributes （CMAs） were screened by variable importance in the projection （VIP） indexes.The results demonstrated that the properties of powders including hygroscopicity, angle of repose, Hausner ratio, Carr index, D50 and loss on drying affected the granule size. Besides, Ginkgo biloba granules were compressed into tablets. In view of tensile strength analysis, the raw materials＇ quality variation did not result in decrease of tensile strength of the ginkgo leaf tablets. The design space of critical quality attributes （CQAs） and the process design space which could cope with raw materials＇ quality variation were proved to be robust.