Trehalose crystallization during freeze-drying: Implications on lyoprotection

Prakash Sundaramurthi, Raj Suryanarayanan

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70 Scopus citations


Lyoprotectants are stabilizers used to prevent denaturation of proteins during freeze-drying and subsequent storage. In order to be effective, lyoprotectants must be retained amorphous. The physical state of the lyoprotectant is usually characterized by powder X-ray diffractometry of the dried cake. While trehalose is widely used as a lyoprotectant, we report its crystallization during freeze-drying and point out why it may not become evident from characterizing the final lyophile. When an aqueous trehalose solution was cooled to -40° C, ice was the only crystalline phase observed. However, upon annealing at -18° C, crystallization of trehalose dihydrate was evident. During drying, the dihydrate dehydrated to substantially amorphous anhydrate. Therefore, analyzing the final dried product will not reveal crystallization of the lyoprotectant during freeze-drying. In light of the observed phase separation of trehalose in frozen solutions, its ability to serve as a lyoprotectant warrants further investigation.

Original languageEnglish (US)
Pages (from-to)510-514
Number of pages5
JournalJournal of Physical Chemistry Letters
Issue number2
StatePublished - Jan 21 2010


  • Biophysical chemistry


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