The accurate prediction of the crystal structure(s) that an organic molecule can be arranged into remains an unsolved theoretical problem of significant importance to industries delivering products in crystalline forms. From a thermodynamic standpoint, polymorphs can be identified as minima in the free energy landscape, motivating the development of crystal structure prediction (CSP) methods. CSP computational methods aim to determine the most stable crystal structure and other metastable forms, with the correct order of stability. Despite recent advances, most state-of-the-art CSP methods rely on lattice energy instead of Gibbs free energy to rank plausible crystal structures. Methods for evaluating the vibrational free energy of predicted crystals either employ computationally expensive atomistic DFT-d calculations or utilise force fields that adopt a rigid body treatment, neglecting intramolecular contributions.

In this thesis, we expand the applicability of the free energy calculation method proposed by Vasileiadis [1] to organic compounds that exhibit molecular flexibility. The proposed workflow for computing the Helmholtz free energy of molecular crystals, involves lattice energy minimisation using an atomistic force field and free energy calculation employing our in-house CrystalDynamics algorithm. The free energy calculation method is based on the harmonic approximation of lattice dynamics theory. The analytical derivations for the electrostatic expressions contribute to the development of an efficient yet accurate energy model applicable to a large number of structures generated in CSP studies. We apply the proposed free energy workflow to refine the CSP landscapes of three molecules of progressively increasing size and flexibility, as well as a set of experimental crystal structures of polymorphic flexible molecules with well-characterised enantiotropic transition temperatures. The workflow presented in this thesis can be utilised as a final refinement stage for CSP-generated landscapes of flexible molecules, bridging the gap between static lattice energies computed at 0 K and temperature-dependent free energies.