Dynamics and Thermodynamics of Ibuprofen Conformational Isomerism at the Crystal/Solution Interface

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 so...