Product Development, Research and Development, GlaxoSmithKline, UK.
Product Development, Research and Development, GlaxoSmithKline, UK.
Int J Pharm. 2015;486(1-2):112-20. doi: 10.1016/j.ijpharm.2015.03.040. Epub 2015 Mar 19.
Dissolution is invariably identified as a critical quality attribute for oral solid dosage forms, since it is related to when a drug is available for absorption and ultimately exert its effect. In this paper, the influence of granule and compression variability introduced by a design of experiments on the entire dissolution profile was studied with an innovative multivariate tool: bi-directional projections to orthogonal structures (O2PLS). This method enabled a more holistic process understanding compared to conventional approaches where only a single response is used to quantify dissolution. The O2PLS analysis of tablet manufacturing data showed that the disintegration phase of dissolution (10-15 min) was controlled by granule attributes and tablet hardness, while the later phase (15-30 min) was solely controlled by granule attributes. The bidirectional nature of the O2PLS model made it more fit for exploratory purposes, but decreased predictive ability. This approach does not require prior knowledge on the dissolution mechanism and is therefore particularly suited for exploratory studies gaining process understanding during early phase development. The outcome can then guide the selection of attributes, parameters and their ranges for the development of predictive models, e.g., models to define a suitable design space for the process.
溶出度是口服固体制剂的关键质量属性，因为它与药物何时可被吸收并最终发挥作用有关。在本文中，研究了通过实验设计引入的颗粒和压缩变异性对整个溶出曲线的影响，使用了一种创新的多元工具：双向正交结构投影（O2PLS）。与传统方法相比，该方法能够更全面地了解工艺，传统方法仅使用单一响应来定量溶出度。片剂制造数据的 O2PLS 分析表明，溶出度的崩解阶段（10-15 分钟）受颗粒属性和片剂硬度控制，而后期阶段（15-30 分钟）仅受颗粒属性控制。O2PLS 模型的双向性质使其更适合探索性目的，但预测能力降低。该方法不需要事先了解溶解机制，因此特别适合在早期开发阶段进行探索性研究以获得工艺理解。结果可以指导选择属性、参数及其范围，以开发预测模型，例如定义过程合适设计空间的模型。
