A potential drawback with the use of mannitol as a bulking agent is its existence as mannitol hemihydrate (MHH; C6H14O6·0.5H2O) in the lyophile. Once formed during freeze-drying, MHH dehydration may require secondary drying under aggressive conditions which can be detrimental to the stability of thermolabile components. If MHH is retained in the lyophile, the water released by MHH dehydration during storage has the potential to cause product instability. We systematically identified the conditions under which anhydrous mannitol and MHH crystallized in frozen systems with the goal of preventing MHH formation during freeze-drying. When mannitol solutions were cooled, the temperature of solute crystallization was the determinant of the physical form of mannitol. Based on low temperature X-ray diffractometry (using both laboratory and synchrotron sources), MHH formation was observed when solute crystallization occurred at temperatures ≤ -20 °C, while anhydrous mannitol crystallized at temperatures ≤ -10 °C. The transition temperature (anhydrate - MHH) appears to be ∼-15 °C. The use of a freeze-dryer with controlled ice nucleation technology enabled anhydrous mannitol crystallization at ∼-5 °C. Thus, ice crystallization followed by annealing at temperatures ≤ -10 °C can be an effective strategy to prevent MHH formation.
|Original language||English (US)|
|Number of pages||7|
|Journal||European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft für Pharmazeutische Verfahrenstechnik e.V|
|State||Published - Oct 2013|
Bibliographical noteFunding Information:
Part of the work was funded by the William and Mildred Peters Endowment Fund. We are very thankful to Leslie Mather and Mark Shon from SP Scientific for conducting a freeze-drying cycle in a pilot-scale freeze-dryer. The XRD studies were carried out at the College of Science and Engineering Characterization Facility, University of Minnesota, which receives partial support from NSF through the MRSEC program. We thank Linda Sauer and Mike Manno for technical assistance during the XRD studies. Khushboo Kothari and Vishard Ragoonanan are thanked for their useful comments. Use of the Advanced Photon Source, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the U.S. DOE under Contract No. DE-AC02-06CH11357. We thank Douglas Robinson and Jong-Woo Kim for their help during the beamline experiments.
© 2013 Elsevier B.V.