The reversed-phase chromatographic behavior of the powerful new anti-migraine drug rizatriptan benzoate and its potential impurities has been studied. Molecular dynamics calculations were used to explain the elution order of the two regioisomers of rizatriptan formed during its synthesis in terms of conformational differences. Further, van't Hoff plots for a mixture of the two regiosiomers and one potential process impurity were non-linear (R = 0.937 - 0.965) when chromatographed on an SB-Phenyl column. However, van't Hoff plots for the same analytes were linear (R ≥ 0.996) when chromatographed on an C8column. The break in the van't Hoff plots generated with an SB-Phenyl phase occurs at ambient temperature (∼25°C) and is attributed to changes in stationary phase morphology as a function of temperature.