Multivariate modelling to study the effect of the manufacturing process on the complete tablet dissolution profile.

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.