Solid state chemical instability of an asparaginyl residue in a model hexapeptide

J Pharm Sci Technol. 1994 May-Jun;48(3):167-23.

Abstract

The chemical stability of an Asn-hexapeptide (Val-Tyr-Pro-Asn-Gly-Ala) in lyophilized formulations was evaluated as a function of the pH of the bulk solution, temperature, and residual moisture content in a factorial study. Degradation pathways and product distribution in solid state were determined and characterized. It was shown in this study that the pH of the starting solution had a significant effect on the rate of deamidation and product distribution. In general, better stability for the Asn-hexapeptide was achieved at a slightly acidic pH range (3-5) in the solid state. The effects of residual moisture level and temperature on peptide stability proved to be less significant. A statistically significant two-factor interaction indicated that the pH of formulation solution determined the extent to which the peptide stability depends on moisture level and temperature. In general, the degradation of the Asn-hexapeptide in the solid state was similar to that observed in solution, except for the observation that no isoAsp-hexapeptide was detected at pH 5.0 in the solid state, whereas this was the major degradation product in solution.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Asparagine / chemistry*
  • Chemistry, Pharmaceutical
  • Drug Stability
  • Factor Analysis, Statistical
  • Freeze Drying
  • Hydrogen-Ion Concentration
  • Hydrolysis
  • Oligopeptides / chemistry*
  • Oligopeptides / pharmacokinetics
  • Peptide Fragments / chemistry*
  • Peptide Fragments / pharmacokinetics
  • Temperature

Substances

  • Oligopeptides
  • Peptide Fragments
  • valyl-tyrosyl-prolyl-asparaginyl-glycyl-alanine
  • Asparagine