Abstract
The formulation of oral solid dosage forms can have a significant impact on drug bioavailability, particularly for poorly soluble drugs. However, traditional formulation development relies heavily on extensive experimental testing, which limits its efficiency and effectiveness in oral drug product design. In this study, we present an integrated framework to support rational formulation design and exploration of optimal dosage regimens. This framework combines population balance-based tablet disintegration and dissolution modeling with physiologically based pharmacokinetic (PBPK) modeling to link critical material attributes (CMAs) with the pharmacokinetic response. The anticoagulant drug rivaroxaban is selected as a model compound for calibration and deployment of the framework, enabling systematic investigation of the effects of crystal size distribution (CSD) and tablet porosity on in vivo performance. The results demonstrate that CSD has a pronounced impact on in pharmacokinetics, whereas tablet porosity exhibits a smaller but non-negligible effect. Furthermore, optimization is implemented to identify the optimal dose amount under a given formulation for producing the desired pharmacokinetic profile for average patient group, demonstrating the potential of this framework for the digital design of both drug efficacy and treatment strategies.