Antagonist [Arg6, D-Trp7,9, MePhe8]-substance P {6-11} was subjected to a systematic stability study in which kinetic parameters were obtained for the degradation of this hexapeptide under several well-defined conditions. The influences of pH, temperature, ionic strength, buffer concentration, and initial concentration of the peptide on the reaction rate constant, kobs, were investigated with a stability-indicating reversed-phase high-performance liquid chromatographic system. From the pH-log kobs degradation profile, obtained at 63 degrees C, it appears that antagonist [Arg6, D-Trp7,9, MePhe8]-substance P {6-11} shows its maximum stability around pH 4.2. The half-life at this pH and temperature is 150 days. In both the hydroxyl- and proton-catalyzed parts of the pH-log kobs degradation profile, the influence of temperature was investigated and Arrhenius plots were constructed. The activation energies in both parts were comparable; however, the frequency factor in the hydroxyl-catalyzed part was 3.3 x 10(4) times higher than in the proton-catalyzed part. Eyring analysis of the data reveals that in both acidic and alkaline media the overall degradation was endotherm (delta H++ as well as delta G++ positive between 273 and 373 degrees K) and the entropy was negative. Increasing ionic strengths in acidic media causes an increase in kobs, while in alkaline media the kobs decreases with increasing ionic strength. Increasing buffer concentrations of acetate, phosphate, and carbonate led to an increase of kobs values. Drug concentrations up to 1 mg/ml at pH 10.8 and constant temperature and ionic strength have no influence on the overall degradation rate. At higher concentrations, above 1 mg/ml, kobs decreases.(ABSTRACT TRUNCATED AT 250 WORDS)