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

An investigation into the subambient behavior of aqueous mannitol solutions using differential scanning calorimetry, cold stage microscopy, and X-ray diffractometry
June 2003
icky L. Kett 1, Shaun Fitzpatrick 2, Brett Cooper 2, Duncan Q.M. Craig 1
1The School of Pharmacy, The Queen's University of Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland
2Merck Sharp and Dohme Research Laboratories, Hertford Road, Hoddesdon, Herts EN11 9BU, UK
Journal of Pharmaceutical Sciences, Volume 92, Issue 9 , Pages 1919 - 1929
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Abstract
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 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 form. The study has also shown that DSC, CSM, and XRD are useful complementary techniques for the study of frozen systems. ? 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:1919-1929, 2003
Keywords
thermal analysis ? cryoprotectant ? calorimetry (DSC) ? lyophilization ? amorphous ? mannitol ? microscopy ? X-ray diffractometry