Small Molecules Technical Development, F. Hoffmann-La Roche Ltd., Basel, Switzerland; Laboratory of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Ghent University, Belgium.
Small Molecules Technical Development, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Int J Pharm. 2018 Jul 10;545(1-2):128-143. doi: 10.1016/j.ijpharm.2018.04.017. Epub 2018 Apr 21.
The overall objective of this work is to understand how excipient characteristics influence the drug product quality attributes and process performance of a continuous twin screw wet granulation process. The knowledge gained in this study is intended to be used for Quality by Design (QbD)-based formulation design and formulation optimization. Three principal components which represent the overarching properties of 8 selected pharmaceutical fillers were used as factors, whereas factors 4 and 5 represented binder type and binder concentration in a design of experiments (DoE). The majority of process parameters were kept constant to minimize their influence on the granule and drug product quality. 27 DoE batches consisting of binary filler/binder mixtures were processed via continuous twin screw wet granulation followed by tablet compression. Multiple linear regression models were built providing understanding of the impact of filler and binder properties on granule and tablet quality attributes (i.e. 16 DoE responses). The impact of fillers on the granule and tablet responses was more dominant compared to the impact of binder type and concentration. The filler properties had a relevant effect on granule characteristics, such as particle size, friability and specific surface area. Binder type and concentration revealed a relevant influence on granule flowability and friability as well as on the compactability (required compression force during tableting to obtain target hardness). In order to evaluate the DoE models' validity, a verification of the DoE models was performed with new formulations (i.e. a new combination of filler, binder type and binder concentration) which were initially not included in the dataset used to build the DoE models. The combined PCA (principle component analysis)/DoE approach allowed to link the excipient properties with the drug product quality attributes.
本工作的总体目标是了解赋形剂特性如何影响连续双螺杆湿法造粒过程的药物产品质量属性和工艺性能。本研究中获得的知识旨在用于基于质量源于设计（QbD）的配方设计和配方优化。使用三个代表 8 种选定药用赋形剂综合性质的主成分作为因素，而因素 4 和 5 则代表实验设计（DoE）中的粘合剂类型和粘合剂浓度。将大多数工艺参数保持不变，以最大程度地减少它们对颗粒和药物产品质量的影响。通过连续双螺杆湿法造粒加工了 27 个 DoE 批次，随后进行片剂压缩。建立了多元线性回归模型，以了解赋形剂和粘合剂性质对颗粒和片剂质量属性的影响（即 16 个 DoE 响应）。与粘合剂类型和浓度的影响相比，赋形剂对颗粒和片剂响应的影响更为显著。赋形剂特性对颗粒特性（如粒径、脆性和比表面积）有相关影响。粘合剂类型和浓度对颗粒流动性和脆性以及可压缩性（片剂压制以获得目标硬度所需的压缩力）有相关影响。为了评估 DoE 模型的有效性，使用最初未包含在用于构建 DoE 模型的数据集中的新配方（即赋形剂、粘合剂类型和粘合剂浓度的新组合）对 DoE 模型进行了验证。PCA（主成分分析）/DoE 组合方法允许将赋形剂特性与药物产品质量属性联系起来。
