Characterizing and measuring the ice nucleation kinetics of aqueous solutions in vials

The stochastic nature of ice nucleation presents a major challenge in freezing and freeze-drying processes of biopharmaceuticals in vials. During freezing, nucleation events occur in the vials of a batch at different times and temperature, which has to be accounted for in process design. This work paves the way towards model-based freezing process design, by presenting a method to estimate nucleation kinetic parameters and their uncertainty from experimental data generated in a parallelized mid-throughput batch-crystallizer. The methodology extends the conventional stochastic description of ice nucleation by considering both the inherent stochasticity, and the variability in heterogeneous nucleation sites among vials. Model validation revealed a nearly quantitative agreement for the predictions of the extended model with experimental data, and a qualitative one for the conventional model. While this work focuses on ice nucleation kinetics, the rigorous analysis of the experimental uncertainty may also be of relevance for nucleation studies in related fields, such as industrial crystallization.CO 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Automated summary

The stochastic nature of ice nucleation poses a challenge in the freezing and freeze-drying processes of biopharmaceuticals in vials. This study presents a method to estimate nucleation kinetic parameters and their uncertainty in order to facilitate model-based freezing process design. The methodology accounts for both the inherent stochasticity and variability in nucleation sites among vials, and the extended model demonstrates good agreement with experimental data.