Impact of Reactant Dissolution in the Kinetics of a Catalytic Hydrogenation for the Production of Argatroban

Abstract

An experimental study was performed for a fed-batch catalytic hydrogenation for the production of Argatroban. The penultimate expensive and scarcely available intermediate is characterized by a slow dissolution rate that evolves in parallel with the reaction process. The study investigated the coupling between the reaction and dissolution kinetics. In these circumstances, the standard Area Percentage method in HPLC was found to be misleading, requiring calibration and then absolute peak area measurements to correctly identify the dissolution rate and thus the actual chemical kinetics. Experiments quantified the role of the temperature, stirring rate, and catalyst loading. Shifting from 40 to 80 °C reduced the batch time by 58%, although higher temperatures promoted the formation of undesired impurities. Stirring rate controlled the initial reaction phases when reagent dissolution is critical. Catalyst loading is key in reducing batch time. The increase in catalyst loading was proved to affect the reagent dissolution rate, by increasing the collision frequency between reagent and catalyst particles. A refined first-principles model, incorporating the effect of the catalyst amount on the dissolution mass transfer coefficient, significantly improved the accuracy of dissolution predictions and enabled better identification of the intrinsic reaction kinetics. The addition of a microkinetic description further improved the predictions of intermediates and products.