ISBN 9783843956871

978-3-8439-5687-1, Reihe Thermodynamik

Adrian Krummnow
Phase Separation, Crystallization and Dissolution of Ritonavir/PVPVA Amorphous Solid Dispersions

176 Seiten, Dissertation Technische Universität Dortmund (2025), Softcover, A5

Zusammenfassung / Abstract

The physical stability and release mechanism of amorphous solid dispersions (ASDs) can be strongly influenced by phase separation and crystallization. In this work, paracetamol, naproxen and ritonavir (RIT) were chosen as model active pharmaceutical ingredients (APIs) and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) as model polymer. The phase behavior of ternary API/polymer/water systems was predicted using Perturbed-Chain Associating Fluid Theory (PC-SAFT) parameters verified for the binary subsystems. The miscibility gap of the RIT/PVPVA/water system was precisely validated using a newly developed approach based on glass-transition temperature measurements, the Kwei equation, and the law of mass conservation. Raman mapping enabled, for the first time, quantifying the kinetics of water-induced amorphous phase separation in RIT/PVPVA ASDs and the compositions of the two evolving amorphous phases. The in situ measured compositions of both phases also excellently agreed with the ternary phase diagram of RIT/PVPVA/water predicted by PC-SAFT. The observed collapse of RIT release from RIT/PVPVA ASDs was profoundly explained based on the validated phase diagram. Both liquid–liquid phase separation in the dissolution medium, as well as amorphous phase separation in the ASD, were linked back to the same thermodynamic origin. Nanodroplet formation in the dissolution medium could be explained as the liquid–liquid phase separation, as predicted by PC-SAFT. Crystal-nucleation and crystal-growth experiments were thermodynamically analyzed to elucidate the low crystallization tendency of RIT in solutions. For the first time, the interfacial tension between crystalline RIT and the solution was determined via Classical Nucleation Theory. One set of kinetic parameters was fitted to crystal-growth experiments to precisely predict the influence of PVPVA using a power law. Solubility measurements validated solubilities and thermodynamic driving forces calculated via PC-SAFT.