An investigation into the subambient behavior of aqueous mannitol solutions using differential scanning calorimetry, cold stage microscopy, and X-ray diffractometry

Vicky L. Kett, Shaun Fitzpatrick, Brett Cooper, Duncan Q. M. Craig

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The subambient behavior of aqueous mannitol solutions is of considerable relevance to the preparation of freeze dried formulations. In this investigation the properties of 3% w/v mannitol solutions were investigated using differential scanning calorimetry (DSC), cold stage microscopy (CSM), and X-ray diffraction (XRD) to identify the thermal transitions and structural transformations undergone by this system. It was found that on cooling from ambient the system formed ice at circa -20°C while a further exotherm was seen at approximately -30°C. Upon reheating an endotherm was seen at circa -30°C followed immediately by an exotherm at circa -25°C. Temperature cycling indicated that the thermal transitions observed upon reheating were not reversible. Modulated temperature DSC (MTDSC) indicated that the transitions observed upon reheating corresponded to a glass transition immediately followed by recrystallization, XRD data showed that recrystallization was into the ß form. Annealing at -35°C for 40 min prior to cooling and reheating resulted in a maximum enthalpy being observed for the reheating exotherm. It is concluded that on cooling 3% w/v aqueous mannitol solutions an amorphous phase is formed that subsequently recrystallises into the ß form. The study has also shown that DSC, CSM, and XRD are useful complementary techniques for the study of frozen systems.
Original languageEnglish
Pages (from-to)1919-1929
Number of pages11
JournalJournal of Pharmaceutical Sciences
Issue number9
Publication statusPublished - 26 Jun 2003


  • thermal analysis
  • microscopy
  • calorimetry (DSC)
  • lyophilization
  • X-ray diffractometry
  • cryoprotectant
  • mannitol
  • amorphous

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