Molecular Dynamics Simulations Predict Centimeter-Scale Shear-Flow Separation of Flexible Drug Enantiomers Within Hours

The study deploys all-atom molecular dynamics on optimized gas-phase geometries solvated in explicit water and organic solvents, applying constant shear rates to compute the resistance tensor and scalar molecular pitch for each conformer. Flexibility produces pitch distributions from conformational sampling, yet mean pitch values remain within 5% of rigid optimized structures across solvents, with shear exerting negligible further perturbation. Translational diffusion opposes separation at molecular scales, but net drift velocities still yield linear enrichment over 10-ns trajectories.

This approach sidesteps traditional chromatographic or crystallization methods that often require expensive chiral auxiliaries, offering a purely mechanical route grounded in the tensorial coupling between molecular chirality and fluid vorticity. Prior rigid-body theories underestimated conformational entropy effects; the present work shows those effects average out, preserving separability for drug-like molecules whose pharmaceutical activity depends on single enantiomers.

Next steps include scaling to macroscopic Taylor-Couette devices operating at laminar Reynolds numbers below 100, with channel widths of 1-2 mm and shear rates tuned to 10^4-10^5 s^-1. Validation requires tracking enantiomeric excess via circular dichroism or chiral HPLC at multiple radial positions after 1-5 hours of continuous flow.

Key limitation remains the nanosecond simulation timescale versus predicted hour-long macroscale runs; longer trajectories or coarse-grained models with hydrodynamic interactions would strengthen extrapolation.