Mutual Influence of Mannitol and Trehalose on Crystallization Behavior in Frozen Solutions

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34 Scopus citations


Purpose: Phase separation of trehalose during freeze-drying could render it ineffective as a lyoprotectant. The bulking agent, mannitol, on the other hand, should crystallize readily upon freezing. It is therefore imperative to understand the mutual interaction of these sugars during freezing to ensure preservation of the API during freeze-drying. Methods: We investigated the effect of mannitol to trehalose ratio (R) on the crystallization behavior of both solutes using Differential Scanning Calorimetry, X-Ray Crystallography and FTIR Spectrosopy during controlled freezing and annealing. Results: When R = 1, crystallization of both mannitol (as hemihydrate) and trehalose (as α-anhydrate) were observed. When R ≥ 1, extent of mannitol crystallization was directly proportional to the value of R. When R < 1, trehalose completely suppressed mannitol crystallization. At R > 1, the freeze concentrate was heterogeneous and characterized by two glass transitions – the lower temperature transition (Tg”) attributed to systems containing “extra” unfrozen water. When heated above Tg”, crystallization of mannitol and the associated unfrozen water resulted in Tg’ (glass transition temperature of the freeze-concentrate).

Original languageEnglish (US)
Pages (from-to)1413-1425
Number of pages13
JournalPharmaceutical research
Issue number6
StatePublished - Jun 1 2016

Bibliographical note

Publisher Copyright:
© 2016, Springer Science+Business Media New York.


  • IR spectroscopy
  • X-ray diffractometry
  • crystallization
  • frozen
  • mannitol
  • microscopy
  • trehalose


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