The Reversed-Phase Liquid Chromatographic Behavior Of The New 5-HT₁D Receptor Agonist Rizatriptan Benzoate and Its potential Process Impurities

Abstract

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 C₈ column. 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.

The SB-Phenyl phase is believed to orient itself in a much more rigid state at sub-ambient temperatures than at temperatures above ambient, which results in the observed reduction in the enthalpy of interaction for analytes at sub-ambient temperature. A corresponding decrease in separation factor (ln α) between rizatriptan regioisomers with increasing temperature is observed as the shape selectivity of the SB-phenyl stationary phase decreases.