Modeling and experimental evaluation of spherical particle dissolution

Dissolution testing is an important tool in drug development because drug particle dissolution can be rate-limiting in drug absorption, which affects bioavailability and bioequivalence. Three classical particle dissolution models (i.e., cube-root, square-root or two-thirds-root of weight undissolved expressions) are often used to describe particle dissolution profiles. New particle dissolution models were developed and experimentally evaluated in this work.; A general solution for diffusion-controlled spherical particle dissolution was obtained for the diffusion layer model which unified the three classical particle dissolution models. Simulations showed that the three classical models are specific cases of the general model which depend on the ratio of particle size to diffusion layer thickness. The general model also predicted that surface area normalized dissolution rate depends on surface curvature. Dissolution data were obtained using a flow-through dissolution system with spherical benzocaine particles prepared using a hot-melt dispersion method. The dissolution results confirmed the applicability of the general model and that dissolution rate per unit area increases as particle radius decreases.; The diffusion layer model lacks predictive power because diffusion layer thickness cannot be independently determined. Convective diffusion dissolution models are mathematically more complex but have better predictive power. Using convective diffusion assumptions for spherical particle dissolution under constant laminar flow led to a five-ninth-root of weight undissolved expression with all parameters in the equation being capable of being independently determined. Analysis of the benzocaine particle dissolution data showed that the predicted initial dissolution rates were 20–50% lower than experimental values. Sources of prediction error were analyzed and a model correction method was evaluated.; The convective diffusion model was also applied to particle dissolution suspended in a flowing dissolution medium producing variable flow velocity during dissolution. A new cube-root expression was obtained which has a different definition for the dissolution rate constant compared to the Hixson-Crowell cube-root law. This model was evaluated using the flow-through dissolution system with a cone-shaped dissolution cell to simulate a particle falling in the dissolution medium. The theoretical predictions agreed well with the experimental dissolution data.