The solvolysis kinetics of a developmental active pharmaceutical ingredient (API) were investigated using a high temperature (HT)-HPLC reactor approach to determine whether it might be possible to use the technique to efficiently screen the relative stabilities of typical APIs (particularly those that are stable at the column temperatures achievable on most HPLC systems and over durations of less than 60 min—a reasonable upper limit for typical method run time). It was discovered that the on-column API degradation kinetics better obeyed a second-order model than a first-order one. Employing a newly developed mathematical treatment, the apparent activation energy for the process was determined to be 85.7 ± 1.6 kJ/mol; the apparent frequency factor was found to be (3.9 ± 0.4) × 104 s−1. The retention mechanism of the API on the C18-modified zirconia column (ZirChrom® Diamondbond™-C18) was investigated using a van’t Hoff analysis. It was discovered that the logarithm of the retention factor (following correction for the gradient elution of the assay method) exhibited a quadratic dependence on the reciprocal of the absolute temperature. While the retention was found to be predominantly enthalpically driven over the majority of temperatures investigated in this study (ranging from 40 to 200 °C), a regression fit of the curve predicted a maximum at ∼20 °C, indicative of a transition from predominantly enthalpically controlled retention to a mainly entropically driven mechanism. A table summarizing the thermodynamic retention parameters at each experimental column temperature is provided. Finally, the preliminary application of the HT-HPLC reactor approach to the study of degradation kinetics of other APIs is discussed in terms of some unexpected findings obtained using the zirconia column.