Statistical mechanical approximations to more efficiently determine polymorph free energy differences for small organic molecules

TL;DR

This paper introduces computationally efficient methods for estimating polymorph free energy differences in organic crystals, bridging the gap between simple approximations and full thermodynamic calculations, with significant cost savings and minimal accuracy loss.

Contribution

It proposes intermediate methods that balance accuracy and computational expense, improving polymorph stability predictions in crystal structure prediction.

Findings

13 out of 29 systems restructured to lower energy minima when heated using REMD.

Proposed methods save 42-80% of computational cost with small error (~0.16 kcal/mol).

Boltzmann weighting of harmonic free energy in REMD trajectories is effective for screening.

Abstract

Methods to efficiently determine the relative stability of polymorphs of organic crystals are highly desired in crystal structure predictions (CSPs). Current methodologies include use of static lattice phonons, quasi-harmonic approximation (QHA), and computing the full thermodynamic cycle using replica exchange molecular dynamics (REMD). We found that 13 out of the 29 systems minimized from experiment restructured to a lower energy minima when heated using REMD, a phenomena that QHA 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 pseudosupercritical path approach. In particular, a method that Boltzmann weights the harmonic free energy of the trajectory of an REMD replica appears to be an appropriate intermediate between QHA and full thermodynamic cycle using MD when screening crystal polymorph stability.