The Mass Transfer Paradox in the Multiscale Analysis of a Pharmaceutical Debenzylation Reaction

Process development and optimization of multiphase reactions is often challenging due to the complex interplay between reaction kinetics and mass transfer. This work analyzes an industrial-scale pharmaceutical debenzylation of an amine-containing precursor catalyzed by a Pd/C catalyst. Using historical lab-scale data, a kinetic model was constructed that reveals competitive adsorption between hydrogen and the precursor, resulting in a reduced debenzylation rate at higher dissolved hydrogen concentrations. When accounting for gas–liquid mass transfer at the pilot scale, lower pressures and stirring speeds limit hydrogen availability due to mass transfer, while higher pressures and stirring speeds increase the dissolved hydrogen concentration, inducing more pronounced adsorption competition and, hence, reducing the reaction rate. These findings indicate the existence of an optimal intermediate operational window that minimizes conversion times by balancing hydrogen availability against catalyst inhibition. Methodologically, this work highlights how multiscale modeling based on historical lab and pilot data can improve industrial-scale predictions and supports more efficient, better-understood pharmaceutical manufacturing.