Semi-mechanistic reduced order model of pharmaceutical tablet dissolution for enabling Industry 4.0 manufacturing systems.

We propose a generalization of the Weibull dissolution model, referred to as generalized Weibull dissolution model, that seamlessly captures all three fractional dissolution rates experimentally observed in pharmaceutical solid tablets, namely decreasing, increasing, and non-monotonic rates. This is in contrast to traditional reduced order models, which capture at most two fractional dissolution rates and, thus, are not suitable for a wide range of product formulations hindering, for example, the adoption of knowledge management in the context of Industry 4.0. We extend the generalized Weibull dissolution model further to capture the relationship between critical process parameters (CPPs), critical materials attributes (CMAs), and dissolution profile to, in turn, facilitate real-time release testing (RTRT) and quality-by-control (QbC) strategies. Specifically, we endow the model with multivariate rational polynomials that interpolate the mechanistic limiting behavior of tablet dissolution as CPPs and CMAs approach certain values of physical significance (such as the upper and lower bounds of tablet porosity or lubrication conditions), thus the semi-mechanistic nature of the reduced order model. Restricting attention to direct compaction and using various case studies from the literature, we demonstrate the versatility and the capability of the semi-mechanistic ROM to estimate changes in dissolution due to process disturbances in tablet weight, porosity, lubrication conditions (i.e., the total amount of shear strain imparted during blending), and moisture content in the powder blend. In all of the cases considered in this work, the estimations of the model are in remarkable agreement with experimental data.