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Measuring the Densities of Aqueous Glasses at Cryogenic Temperatures
Published on: June 28, 2017
Rethinking freezing: the misconception of nucleation temperature and ice crystal formation in freeze-drying
Tigran Kharatyan1, Srikanth R Gopireddy2, Regina Scherließ3
1Department of Pharmaceutics and Biopharmaceutics, Kiel University, 24118 Kiel, Germany; Pharmaceutical Development, Daiichi Sankyo Europe GmbH, 85276 Pfaffenhofen an der Ilm, Germany.
International Journal of Pharmaceutics
|May 13, 2026
Summary
Nucleation temperature is not the primary driver of pore size in freeze-dried products. The duration of the exothermic ice formation event, not just nucleation temperature, significantly impacts ice crystal structure and final product microstructure.
Area of Science:
- Pharmaceutical Sciences
- Materials Science
- Physical Chemistry
Background:
- Classical nucleation theory posits nucleation temperature dictates ice crystal size and lyophilisate pore structure.
- This theory overlooks the exothermic nature of ice formation, which influences crystal growth.
- Understanding ice formation dynamics is crucial for controlling lyophilized product microstructure.
Purpose of the Study:
- To investigate the influence of the exothermic ice formation event on ice crystal size distribution.
- To challenge the conventional assumption that nucleation temperature solely determines lyophilisate pore size.
- To assess the impact of thermal treatment during freezing on the final ice crystal structure.
Main Methods:
- Utilized a freeze-drying microscope to observe ice crystal formation.
- Compared rapidly frozen samples with samples undergoing thermal treatment mimicking freeze-dryer conditions.
- Analyzed the relationship between nucleation temperature, temperature rise duration, and ice crystal structure.
Main Results:
- The final ice crystal structure is primarily governed by the duration of the temperature increase during freezing, not solely by nucleation temperature.
- A correlation exists between nucleation temperature and the duration of the temperature rise, indicating an indirect influence.
- The exothermic heat release during ice formation plays a significant role in determining ice crystal morphology.
Conclusions:
- Nucleation temperature's role in freeze-drying is indirect; the duration of the temperature rise is the dominant factor controlling ice crystal structure.
- The exothermic nature of ice formation must be considered for a comprehensive understanding of lyophilization.
- Revising the perspective on nucleation temperature is necessary for optimizing freeze-drying processes and product quality.
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