Antagonist (\left[\mathrm{Arg}^{6}\right.), D-Trp ({ }^{7,9}), MePhe (\left.^{8}\right])-substance P {611) 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 (\mathrm{pH}), temperature, ionic strength, buffer concentration, and initial concentration of the peptide on the reaction rate constant, (k_{\text {obs, }}), were investigated with a stability-indicating reversed-phase high-performance liquid chromatographic system. From the (\mathrm{pH}-\log \boldsymbol{k}{\mathrm{obs}}) degradation profile, obtained at (63^{\circ} \mathrm{C}), it appears that antagonist [ (\mathbf{A r g}^{\boldsymbol{s}}), D-Trp ({ }^{7,9}), MePhe (\left.{ }^{8}\right])-substance (P) [6-11} shows its maximum stability around (\mathrm{pH}) 4.2. The half-life at this (\mathrm{pH}) and temperature is 150 days. In both the hydroxyl- and proton-catalyzed parts of the (\mathrm{pH}-\log k{\mathrm{obg}}) 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 \times 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^{\ddagger}) as well as (\Delta G^{\ddagger}) positive between 273 and (373^{\circ} \mathrm{K}) ) and the entropy was negative. Increasing ionic strengths in acidic media causes an increase in (k_{\text {oba }}), while in alkaline media the (k_{\text {oba }}) decreases with increasing ionic strength. Increasing buffer concentrations of acetate, phosphate, and carbonate led to an increase of (k_{\text {obs }}) values. Drug concentrations up to 1 (\mathrm{mg} / \mathrm{ml}) at (\mathrm{pH} 10.8) and constant temperature and ionic strength have no influence on the overall degradation rate. At higher concentrations, above (1 \mathrm{mg} / \mathrm{ml}, k_{\text {obs }}) decreases. In acidic media ( (\mathrm{pH} 2) ) similar results are obtained. 1995 Academic Press, Inc.