CHEMICAL PATHWAYS OF PEPTIDE DEGRADATION .7. SOLID-STATE CHEMICAL-INSTABILITY OF AN ASPARTYL RESIDUE IN A MODEL HEXAPEPTIDES

The chemical stability of an Asp-hexapeptide (Val-Tyr-Pro-Asp-Gly-Ala) in lyophilized formulations was evaluated as a function of multiple f ormulation variables-specifically pH of the bulk solution, temperature , moisture content, and type of bulking agent (amorphous vs. crystalli ne). The disappearance of the starting Asphexapeptide in the solid sta te conformed to pseudo-first-order reversible kinetics. This type of d egradation profile was accounted for by the product distribution. The factorial experimental design of this study allowed statistical analys is of the effects of individual formulation variable (main effects) as well as those of two-factor interactions on the degradation of the As p-hexapeptide. Analysis of Variance (ANOVA) calculations of the main e ffects indicated that while the influence of pH of the starting soluti on was not statistically significant, residual moisture level, tempera ture, and, especially, type of bulking agent had a significant impact on the solid state chemical reactivity of the hexapeptide. Furthermore , depending on which type of excipient was used in the lyophilized for mulations, residual moisture level and temperature could be important stability variables. These types of factorial experiments have proven to be useful in the rapid identification of significant formulation va riables in a given system and, consequently, in optimization of formul ations .