An HPLC chromatographic reactor approach for investigating the hydrolytic stability of a pharmaceutical compound

The solution-phase hydrolysis kinetics of the Aprepitant (Emend) prodrug, Fosaprepitant Dimeglumine, were investigated using an HPLC chromatographic reactor approach. The term 'chromatographic reactor' refers to the use of an analytical-scale column as both a flow-through reactor and, simultaneously, as separation medium for the reactant(s) and product(s). Recently, we reported a novel mathematical treatment for the kinetic data obtained from chromatographic reactors, which we believe is superior to other treatments in terms of its accuracy, robustness and ease of implementation. In this work, we demonstrate that our treatment may be applied equally well to HPLC reactors, as previously we studied only GC reactors. It is found that the hydrolysis of Fosaprepitant Dimeglumine (FD) has an apparent activation energy of 107 kJ/mol when the reaction is investigated on-column, using the gradient elution conditions of the validated HPLC impurity profile method for this compound. For comparison, the activation energy determined for the same reaction occurring in a quiescent solution consisting of a fixed ratio of acetonitrile-0.1% v/v aqueous H3PO4 (50:50, v/v) is 91 kJ/mol, calculated using direct application of the Arrhenius equation. The data presented show that, when used as a screening tool, chromatographic reactors may be feasible for use in the pharmaceutical industry to quickly gauge the relative stabilities of various compounds with similar degradation pathways.