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Existence of a mannitol hydrate during freeze-drying and practical implications
1Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana 46285, USA.yu_lian@lilly.com
Journal of Pharmaceutical Sciences
|February 9, 1999
Summary
A new mannitol hydrate crystal form emerges during freeze-drying, impacting drying rates and leading to vial-to-vial moisture variations. This metastable hydrate converts to anhydrous forms when heated or exposed to moisture.
Area of Science:
- Pharmaceutical Sciences
- Materials Science
- Physical Chemistry
Background:
- Freeze-drying is a critical process for stabilizing pharmaceutical products.
- Mannitol is a common excipient used in lyophilization.
- Understanding excipient behavior during freeze-drying is essential for formulation development.
Purpose of the Study:
- To identify and characterize a novel mannitol hydrate formed during freeze-drying.
- To investigate the formation conditions and properties of this mannitol hydrate.
- To assess the implications of mannitol hydrate formation on the freeze-drying process and product stability.
Main Methods:
- Freeze-drying of mannitol solutions (1-4% w/v) using a specific temperature and time cycle.
- X-ray powder diffraction (XRPD) for crystallographic analysis.
- Differential Scanning Calorimetry (DSC) for thermal analysis and desolvation behavior.
- Observation of hydrate formation in the presence of sorbitol.
Main Results:
- A previously unknown mannitol hydrate was identified through thermal and crystallographic analysis.
- The hydrate exhibited a unique XRPD pattern, low melting point, and characteristic desolvation behavior.
- Formation was observed during freeze-drying of mannitol solutions and in the presence of sorbitol.
- The mannitol hydrate is metastable, converting to anhydrous forms upon heating or moisture exposure.
Conclusions:
- The formation of mannitol hydrate during freeze-drying is a significant phenomenon.
- This hydrate can influence drying rates and lead to vial-to-vial variations in moisture content.
- Understanding and controlling mannitol hydrate formation is crucial for optimizing freeze-drying cycles and ensuring product uniformity and stability.