Characterization of Membrane-Type Dissolution Profiles of Clinically Available Orally Inhaled Products Using a Weibull Fit and a Mechanistic Model

Abstract

Dissolution rate impacts the absorption rate of poorly soluble inhaled drugs. In vitro dissolution tests that can capture the impact of changes in critical quality attributes of the drug product on in vivo dissolution are important for the development of products containing poorly soluble drugs, as well as modified release formulations. In this study, an extended mathematical model allowing for dissolution of polydisperse powders and subsequent diffusion of dissolved drug across a membrane is described. In vitro dissolution profiles of budesonide, fluticasone propionate, and beclomethasone dipropionate delivered from three commercial drug products were determined using a membrane-type Transwell dissolution test, which consists of a donor and an acceptor compartment separated by a membrane. Subsequently, the profiles were analyzed using the developed mechanistic model and a semi-empirical model based on the Weibull distribution. The two mathematical models provided the same rank order of the performance of the three drug products in terms of dissolution rates, but the rates were significantly different. The faster rate extracted from the mechanistic model is expected to reflect the true dissolution rate of the drug; the Weibull model provides an effective and slower rate that represents not only drug dissolution but also diffusion across the Transwell membrane. In conclusion, the developed extended model provides superior understanding of the dissolution mechanisms in membrane-type (Transwell) dissolution tests.