Effect of Water on the Chemical Stability of Amorphous Pharmaceuticals: 2. Deamidation of Peptides and Proteins.
J Pharm Sci
; 107(1): 42-56, 2018 01.
Article
en En
| MEDLINE
| ID: mdl-28923320
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Péptidos
/
Agua
/
Proteínas
Idioma:
En
Revista:
J Pharm Sci
Año:
2018
Tipo del documento:
Article