Crystallization of mannitol below Tg′ during freeze-drying in binary and ternary aqueous systems

Abira Pyne, Rahul Surana, Raj Suryanarayanan

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84 Scopus citations


Purpose. To characterize the phase transitions in a multicomponent system during the various stages of the freeze-drying process and to evaluate the crystallization behavior below Tg′ (glass transition temperature of maximally freeze-concentrated amorphous phase) in frozen aqueous solutions and during freeze-drying. Methods. X-ray powder diffractometry (XRD) and differential scanning calorimetry (DSC) were used to study frozen aqueous solutions of mannitol with or without trehalose. By attaching a vacuum pump to the low-temperature stage of the diffractometer, it was possible to simulate the freeze-drying process in situ in the sample chamber of the XRD. This enabled real-time monitoring of the solid state of the solutes during the process. Results. In rapidly cooled aqueous solutions containing only mannitol (10% w/w), the solute was retained amorphous. Annealing of frozen solutions or primary drying, both below Tg′, resulted in crystallization of mannitol hydrate. Similar effects were observed in the presence of trehalose (2% w/w). At higher concentrations (≥5% w/w) of this noncrystallizing sugar, annealing below Tg′ led to nucleation but not crystallization. However, during primary drying, crystallization of mannitol hydrate was observed. Conclusions. The combination of in situ XRD and DSC has given a unique insight into phase transitions during freeze-drying as a function of processing conditions and formulation variables. In the presence of trehalose, mannitol crystallization was inhibited in frozen solutions but not during primary drying.

Original languageEnglish (US)
Pages (from-to)901-908
Number of pages8
JournalPharmaceutical research
Issue number6
StatePublished - 2002

Bibliographical note

Funding Information:
Partial financial support from the Parenteral Drug Association Foundation for Pharmaceutical Sciences and from the International Student Work Opportunity Program, University of Minnesota, is greatly appreciated. We thank Dr. Evgenyi Shalaev for his valuable comments.

Copyright 2017 Elsevier B.V., All rights reserved.


  • Annealing
  • Differential scanning calorimetry
  • Frozen
  • Mannitol
  • Trehalose
  • X-ray powder diffractometry


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