A mechanistic framework for predicting tablet disintegration: Integrating the Representative Capillary Evolution...

The disintegration behaviour of pharmaceutical tablets is a critical quality attribute influencing drug release, yet predicting it from formulation and processing parameters remains challenging due to complex underlying mechanisms. This work presents a novel, mechanistically grounded framework aimed at predicting immediate-release tablet disintegration. The framework uniquely integrates insights from advanced experimental techniques with two complementary computational models. Terahertz Pulsed Imaging (TPI) combined with an open immersion cell provides non-invasive, real-time monitoring of internal liquid transport kinetics, crucially accounting for simultaneous matrix erosion. This empirical data anchors the Representative Capillary Evolution Model (RCEM), a top-down model that interprets macroscopic disintegration behaviour through the evolution of a conceptual Representative Capillary (RC) structure, incorporating an Agitation Coefficient (A_coef) to bridge quiescent and agitated test conditions. Complementing this is the Dynamic Void Fraction Evolution Model (DVFEM), a bottom-up model that predicts the time-dependent evolution of the tablet's microstructure and the associated void fraction based on fundamental constituent properties (e.g., particle swelling, dissolution) and formulation details, using a unit cell concept. The RC serves as the unifying element linking DVFEM predictions to RCEM interpretations. An iterative strategy for integrating and calibrating these models is proposed, potentially enhanced by machine learning techniques. The framework offers a pathway to link Critical Material Attributes (CMAs) and Critical Processing Parameters (CPPs) to disintegration performance, aligning with Quality by Design (QbD) principles and holding potential to accelerate pharmaceutical formulation development.