Abstract：
:Role of water in chemical (in)stability is revisited, with focus on deamidation in freeze-dried amorphous proteins and peptides. Two distinct patterns for deamidation versus water have been reported, that is, a consistent increase in rate constant with water, and a "hockey stick"-type behavior. For the latter, deamidation is essentially independent of water at lower water contents and accelerates when water content increases above a threshold value. Two simple kinetic models are developed to analyze literature-reported relationships between water content and deamidation rate constants. One model is based on catalytic role of water clusters in enabling proton transfer, which is a critical reaction step. Water clusters are formed when water content increases above a threshold value, while unclustered (and less catalytically-active) water molecules are predominant at lower water levels. The second model considers the dual role of water, as both a destabilizer via catalysis and a stabilizer of protein native structure. Considering that both models emphasize the importance of local structure and that local structure is intrinsically related to fast (and non-cooperative) relaxation modes, it is plausible to expect correlations between local mobility, such as beta-relaxation, and amorphous chemical instability.
journal_name
J Pharm Scijournal_title
Journal of pharmaceutical sciencesauthors
Ohtake S,Feng S,Shalaev Edoi
10.1016/j.xphs.2017.09.003subject
Has Abstractpub_date
2018-01-01 00:00:00pages
42-56issue
1eissn
0022-3549issn
1520-6017pii
S0022-3549(17)30626-3journal_volume
107pub_type
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