Unravelling the Impact of Process Impurities on the Crystallization of Ritlecitinib Tosylate Using Molecular Dynamics

We investigate the influence of oligomeric impurities on the crystallization of ritlecitinib tosylate, an active pharmaceutical compound, using a combined experimental and molecular modeling approach. Ritlecitinib oligomers, particularly hexamers, were identified as key species hindering crystal growth. Experimental outcomes highlighted the inhibitory effects of oligomers on crystallization kinetics, yield, and physical properties. Simplified free energy methods based on the linear interaction energy model revealed a nonmonotonic relationship between oligomer size and surface affinity, with hexamers having the most prominent tendency to block the surface of ritlecitinib tosylate crystals, thus impacting crystal growth. A competitive Langmuir adsorption isotherm model quantified the reduction in crystal growth rates due to oligomer adsorption, providing a systematic approach to understanding these inhibitory effects. This research enhances our understanding of the molecular mechanisms governing oligomer adsorption, and more generally, impurity adsorption, on crystal surfaces and offers insights for designing crystal growth inhibitors in pharmaceutical applications.