Beyond Enthalpy: Incorporating Vibrational Entropy into Crystal Structure Prediction through Molecular Dynamics

Predicting with certainty which polymorphic form a molecule will adopt during crystallization remains an unsolved challenge. Both quantum and classical Molecular Dynamics (MD) approaches neglect entropic effects that can significantly bias the relative stability and ranking of polymorphic forms. Recovering entropy terms from quantum simulations or MD simulations through thermodynamic integration is typically very demanding.  In this context, incorporating entropy calculations into MD-based crystal structure prediction (CSP) workflows would represent a substantial advancement. To this end, we developed two different algorithms to estimate vibrational entropy contributions from MD simulations of periodic molecular solids.