ISBN 978-3-8439-5772-4

978-3-8439-5772-4, Reihe Thermodynamik

Maximilian Zäh
Influence of Phase Behavior and Water Activity on Lyophilization Processes and Formulations

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

Zusammenfassung / Abstract

Freeze-drying or lyophilization is a crucial process in the pharmaceutical industry, as it significantly contributes to the preservation of temperature-sensitive biopharmaceutics.

In this work, two essential system parameters were studied: the glass-transition temperature and the composition of the amorphous phase during freeze-drying (Tg' and wg'). A novel approach was developed to predict wg' for individual excipients, binary excipient mixtures, and a model protein. This approach was validated using calorimetric measurement methods and a low-temperature suspension balance, demonstrating that the predictions and experimental measurements are consistent.

Additionally, water activity was introduced as an indicator of the stability of freeze-dried formulations. This value accounts for the impact of the glass-transition temperature of the excipients used and the process-dependent residual moisture after drying. It was shown that calculated water activities correlate with the stability of antibody formulations, allowing for the determination of a formulation window for freeze-dried antibody formulations in dependence of water activity. A proposed approach for identifying advantageous formulations helps to avoid trial-and-error processes and was validated through stability studies.

Finally, annealing, an optional process step where an excipient crystallizes before drying, was examined. The crystallization behavior of mannitol and glycine concerning the equilibrium concentration and crystallization kinetics was investigated, and the process development was adapted to the crystallization behavior. This made it possible to determine the temperature range in which annealing is possible and to estimate the necessary annealing time.

In conclusion, this work emphasizes that thermodynamic parameters are crucial for the design of freeze-drying processes and the stabilization of biopharmaceutics.