Solid state chemical instability of an asparaginyl residue in a model hexapeptide.
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.
Oliyai
C
C
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence 66045.
Patel
J P
JP
Carr
L
L
Borchardt
R T
RT
D001216:Asparagine / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D004355:Drug Stability; D005163:Factor Analysis, Statistical; D005612:Freeze Drying; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D009842:Oligopeptides / Q000737:chemistry* / Q000493:pharmacokinetics; D010446:Peptide Fragments / Q000737:chemistry* / Q000493:pharmacokinetics; D013696:Temperature
D009842:Oligopeptides; D010446:Peptide Fragments; C089005:valyl-tyrosyl-prolyl-asparaginyl-glycyl-alanine; D001216:Asparagine