Statistical Mechanical Approximations to More Efficiently Determine Polymorph Free Energy Differences for Small Organic Molecules

Methods to efficiently determine the relative stability of polymorphs of organic crystals are highly desired in crystal structure predictions (CSPs). Current methodologies include calculating the free energy of static lattice phonons, quasi-harmonic approximations (QHA), and computing the full thermodynamic cycle using replica exchange molecular dynamics (REMD). We found that 13 out of the 29 systems minimized from experimental crystal structures restructured to a lower energy minimum when heated and annealed using REMD, a phenomenon that QHA alone cannot capture. Here, we present a series of methods that are intermediate in accuracy and expense between QHA and computing the full thermodynamic cycle, which can save 42–80% of the computational cost and introduces, on this benchmark, a relatively small (0.16 ± 0.04 kcal/mol) error relative to the full thermodynamic cycle. In particular, a method that Boltzmann weights harmonic free energies from along the trajectory of REMD replica exchange appears to be an appropriate intermediate between QHA and the full thermodynamic cycle using MD when screening crystal polymorph stability.