Dynamics and thermodynamics of Ibuprofen conformational isomerism at the crystal/solution interface

Abstract

Conformational flexibility of molecules involved in crystal growth and dissolution is rarely investigated in detail, and usually considered to be negligible in the formulation of mesoscopic models of crystal growth. In this work we set out to investigate the conformational isomerism of ibuprofen as it approaches and is incorporated in the morphologically dominant {100} crystal face, in a range of different solvents - water, 1-butanol, toluene, cyclohexanone, cyclohexane, acetonitrile and trichloromethane. To this end we combine extensive molecular dynamics and well-tempered metadynamics simulations to estimate the equilibrium distribution of conformers, compute conformer-conformer transition rates, and extract the characteristic relaxation time of the conformer population in solution, adsorbed at the solid/liquid interface, incorporated in the crystal in contact with the mother solution, and in the crystal bulk. We find that, while the conformational equilibrium distribution is weakly dependent on the solvent, relaxation times are instead significantly affected by it. Furthermore, differences in the relaxation dynamics are enhanced on the crystal surface, where conformational transitions become slower and specific patways are hindered. This leads to observe that the dominant mechanisms of conformational transition can also change significantly moving from the bulk solution to the crystal interface, even for a small molecule with limited conformational flexibility such as ibuprofen. Our findings suggests that understanding conformational flexibility is key to provide an accurate description of the solid/liquid interface during crystal dissolution and growth, and therefore its relevance should be systematically assessed in the formulation of mesoscopic growth models.