Freezing of Aqueous Solutions and Chemical Stability of Amorphous Pharmaceuticals: Water Clusters Hypothesis.
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Authors
Shalaev, Evgenyi
Soper, Alan
Zeitler, J Axel
Ohtake, Satoshi
Roberts, Christopher J
Pikal, Michael J
Wu, Ke
Boldyreva, Elena
Publication Date
2019-01Journal Title
J Pharm Sci
ISSN
0022-3549
Publisher
Elsevier BV
Volume
108
Issue
1
Pages
36-49
Language
eng
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Shalaev, E., Soper, A., Zeitler, J. A., Ohtake, S., Roberts, C. J., Pikal, M. J., Wu, K., & et al. (2019). Freezing of Aqueous Solutions and Chemical Stability of Amorphous Pharmaceuticals: Water Clusters Hypothesis.. J Pharm Sci, 108 (1), 36-49. https://doi.org/10.1016/j.xphs.2018.07.018
Abstract
Molecular mobility has been traditionally invoked to explain physical and chemical stability of diverse pharmaceutical systems. Although the molecular mobility concept has been credited with creating a scientific basis for stabilization of amorphous pharmaceuticals and biopharmaceuticals, it has become increasingly clear that this approach represents only a partial description of the underlying fundamental principles. An additional mechanism is proposed herein to address 2 key questions: (1) the existence of unfrozen water (i.e., partial or complete freezing inhibition) in aqueous solutions at subzero temperatures and (2) the role of water in the chemical stability of amorphous pharmaceuticals. These apparently distant phenomena are linked via the concept of water clusters. In particular, freezing inhibition is associated with the confinement of water clusters in a solidified matrix of an amorphous solute, with nanoscaled water clusters being observed in aqueous glasses using wide-angle neutron scattering. The chemical instability is suggested to be directly related to the catalysis of proton transfer by water clusters, considering that proton transfer is the key elementary reaction in many chemical processes, including such common reactions as hydrolysis and deamidation.
Keywords
amorphism, chemical stability, deamidation, freeze-drying, lyophilization, protein formulation(s), solid-state, stability, structure, water sorption, Chemical Phenomena, Chemistry, Pharmaceutical, Drug Stability, Freeze Drying, Freezing, Hydrolysis, Solutions, Temperature, Water
Sponsorship
EPSRC EP/N022769/1
Funder references
EPSRC (1198)
Identifiers
External DOI: https://doi.org/10.1016/j.xphs.2018.07.018
This record's URL: https://www.repository.cam.ac.uk/handle/1810/280594
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: http://creativecommons.org/licenses/by-nc-nd/4.0/
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