Separation of Flexible Enantiomers Using Shear Flow

Mechanical separation of enantiomers is an attractive alternative to synthetic methods for producing enantiopure samples. Shear flow that produces solution vorticity has been shown to be a viable means for separating chiral objects on the micro- to nanoscale due to the tensorial nature of the interactions between chiral objects and the surrounding fluid. A recently developed theory of molecular pitch characterizes these interactions using the resistance tensor and predicts the shear-induced separation of drug-like molecules from their optimized molecular geometries. We present a molecular dynamics study on the effects of incorporating molecular flexibility into the molecular pitch framework. We also evaluate the potential for enantiomeric separation of two drug molecules: bicalutamide (Casodex) and montelukast sodium (Singulair). Simulations reveal the emergence of flexibility-induced pitch distributions that result from conformational changes occurring in a realistic solvent environment. However, these distributions are weakly influenced by the solvent identity and the shearing process, producing mean scalar pitch values that are close to those from optimized gas-phase structures. Despite the opposing effects of translational diffusion at the molecular scale, racemic mixtures of flexible enantiomers show linear rates of separation at the 2 ns time scale, and we predict that cm-scale separation can be achieved within hours. Additionally, we provide estimates for parameters of a Taylor-Couette device for generating laminar shear flow, as well as considerations for prospective experiments.