Alternative Methods of Controlling Nucleation in Freeze Drying

  • Roberto PisanoEmail author
Part of the Methods in Pharmacology and Toxicology book series (MIPT)


The control of freezing, and particularly of the nucleation temperature, is one of the most challenging aspects of the development of a lyophilization cycle. Technological advances of recent years have increased the efficiency with which nucleation temperature can be adjusted. This chapter discusses these technologies, as well as some emerging technologies that might play an important role in near future. In particular each technology is presented in terms of easy to be implemented, scalability on industrial units, influence on product morphology, protein preservation, intra-vial and vial-to-vial heterogeneity, and process performance.

Key words

Control Freezing Nucleation 



Hydroxyethyl starch


Specific surface area


Vacuum-induced surface freezing



Pore size, m


Vapour flux, kg m−2 s−1


Molecular weight of water, kg mol−1


Vapour pressure of ice, Pa


Partial pressure of water inside the drying chamber, Pa


Resistance to mass transfer, m s−1


Ideal gas constant, J mol−1 K−1


Glass transition temperature, K


Eutectic temperature, K


Nucleation temperature, K

Greek Letters


Porosity of the lyophilized product, –


Tortuosity of the lyophilized product, –


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Authors and Affiliations

  1. 1.Department of Applied Science and Technology, Molecular Engineering LaboratoryPoliteccnico di TorinoTorinoItaly

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