Chemical stability of peptides in polymers. 2. Discriminating between solvent and plasticizing effects of water on peptide deamidation in poly(vinylpyrrolidone)

doi:10.1021/js9802289

Journal of Pharmaceutical Sciences

Volume 88, Issue 10, October 1999, Pages 1081-1089

https://doi.org/10.1021/js9802289 Get rights and content

Abstract

The mechanistic role of water in the deamidation of a model asparagine‐containing hexapeptide (Val‐Tyr‐Pro‐Asn‐Gly‐Ala) in lyophilized formulations containing poly(vinylpyrrolidone) (PVP) and glycerol was investigated. Glycerol was used as a plasticizer to vary formulation glass transition temperature (T_g) without significantly changing water content or activity. Increases in moisture and glycerol contents increased the rate of peptide deamidation. This increase was strongly correlated with T_g at constant water content and activity, suggesting that increased matrix mobility facilitates deamidation. In rubbery systems (T > T_g), deamidation rates appeared to be independent of water content and activity in formulations with similar T_gs. However, in glassy formulations with similar T_gs, deamidation increased with water content, suggesting a solvent/medium effect of water on reactivity in this regime. An increase in water content also affected the degradation product distribution; less of the cyclic imide intermediate and more of the hydrolytic products, isoAsp‐ and Asp‐hexapeptides, were observed as water content increased. Thus, residual water appears to facilitate deamidation in these solid PVP formulations both by enhancing molecular mobility and by solvent/medium effects, and also participates as a chemical reactant in the subsequent breakdown of the cyclic imide.

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Research ArticlesChemical stability of peptides in polymers. 2. Discriminating between solvent and plasticizing effects of water on peptide deamidation in poly(vinylpyrrolidone)

Abstract

J. Pharm. Sci.

J. Pharm. Sci.

J. Pharm. Sci.

J. Biol. Chem.

Rational design of stable lyophilized protein formulations: Some practical advice

Pharm. Res.

Water sorption and solid‐state stability of proteins

The effect of formulation variables on the stability of freeze‐dried human growth hormone

Pharm. Res.

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Pharm. Res.

Solid‐state stability of human insulin. I. mechanism and the effect of water on the kinetics of degradation in lyophiles from pH 2‐5 solutions

Pharm. Res.

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J. Parenteral Sci. Technol.

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Viscoelastic Properties of Polymers

Formation of glasses from liquids and biopolymers

Science

Research Articles
Chemical stability of peptides in polymers. 2. Discriminating between solvent and plasticizing effects of water on peptide deamidation in poly(vinylpyrrolidone)