Non-linear Mixed Effects Modeling and Simulation for Exploring VariabilitySources in Dissolution Curves: A BCS Class II Case Example

Purpose: Irbesartan is a BCS class II compound that exhibits pH– and buffer capacity–dependent dissolution behavior. The aim of this study was to apply non-linear mixed effects modelling on dissolution data of two immediate release products containing Irbesartan in order to characterize and quantify the sources of inter-dissolution profile variability. Methods: Nonlinear mixed effects modelling was applied to describe the dissolution curves obtained for Irbesartan in three different pH-value media (1.2, 4.5, 6.8) with two different products (reference product: Aprovel® and a generic test product). Simulations performed and the impact of inter-dissolution variability was assessed. Results: The % Irbesartan dissolved to time was found to follow a Weibull distribution. Τhe population scale parameter was estimated 0.252 and the shape parameter was estimated 0.706. The pH-value of the dissolution medium was found to significantly affect the scale parameter, while the formulation was found to affect the shape parameter. Simulations showed that probably some discrepancies in the in vivo performance of the two products can be expected. Conclusion: Through this case study the applicability and usefulness of nonlinear mixed effects modelling in oral drug formulation was highlighted and resides in its ability to identify and quantify sources of variability.