ISBN 9783843956161

978-3-8439-5616-1, Reihe Thermodynamik

Friederike Wolbert
Predicting the Shelf Life of Amorphous Solid Dispersions

146 Seiten, Dissertation Technische Universität Dortmund (2024), Softcover, A5

Zusammenfassung / Abstract

The development of amorphous solid dispersions (ASDs) for poorly water-soluble active pharmaceutical ingredients (APIs) requires an in-depth understanding of factors that influence their shelf life. One key aspect is the stability of the amorphous API in the ASD. Thermodynamic stability refers to whether the amorphous API is stable or metastable (supersaturated), with the latter inevitably leading to crystallization. The kinetic stability describes the time span until crystallization. In this thesis, various factors influencing the stability of ASDs were investigated, including storage conditions (temperature, relative humidity), polymer selection, manufacturing method (spray drying, hot melt extrusion), API load and particle size distribution. Based on the results, a new approach to predict ASD shelf life was developed, combining the Johnson-Mehl-Avrami-Kolmogorov equation with classical nucleation theory. This approach integrates different building blocks: a thermodynamic model (PC-SAFT) to determine the API supersaturation and water sorption, a model to determine the glass transition temperature (Gordon-Taylor equation) and models to determine the viscosity above and below the glass transition (Williams-Landel-Ferry (WLF) equation, Arrhenius equation). Furthermore, two methods for measuring crystallization kinetics – water-sorption measurements and Raman spectroscopy - were compared and cross-validated. The developed approach is applicable for any drug-polymer combination and manufacturing process and allows the prediction of the shelf life of a potential ASD at an early stage of development within a few days. It was successfully verified for ASDs stored at 25 °C and 10% or 60% RH. This study expands the understanding of ASDs and their stability and contributes to the efficient development of pharmaceutical formulations for poorly water-soluble drugs.