Inaccurate Conformational Energies Still Hinder Crystal Structure Prediction in Flexible Organic Molecules

Abstract

Crystal structure prediction driven by density functional theory has become an increasingly useful tool for the pharmaceutical industry and others interested in understanding and controlling organic molecular crystal packing. However, delocalization error in widely used density functionals leads to problematic conformational energies that can cause incorrect predictions of polymorph stabilities. In five examples ranging from small molecules to the polymorphically challenging pharmaceuticals axitinib and galunisertib, the present work demonstrates how inexpensively correcting the intramolecular conformational energies with higher-level electronic structure methods leads to polymorph stability predictions that agree far better with experiment. This approach also provides a valuable diagnostic for when skepticism about predicted polymorph stabilities is warranted.

How many more polymorphs of ROY remain undiscovered

“…Unfortunately, the B86bPBE-XDM energy rankings agree poorly with experiment, similar to what has been found in previous DFT studies of ROY. 24,29,68,70,71 As shown in Figure 3, the B86bPBE-XDM lattice energies exhibit an rms error of 6.1 kJ/mol compared to the relative experimental enthalpies, more than double the error of the CrystalOptimizer potential. Most notably, the red-and orange-colored experimental polymorphs are substantially overstabilized relative to the yellow ones.…”

“…Finally, because delocalization error in generalized gradient approximation (GGA) and hybrid functionals artificially stabilizes more planar conformations of ROY, 29,70,71 a single-point gasphase monomer conformational energy correction was applied to each crystal. 71 These corrections replace the B86bPBE-XDM intramolecular conformational energy with one computed from spin-component-scaled dispersion-corrected second-order Møller-Plesset perturbation theory (SCS-MP2D) at the complete-basis-set limit. 100 This model reproduces benchmark coupled cluster theory conformational energies of ROY well (Figure S3 † ) at modest computational cost.…”

“…This polymorph energy ranking problem stems from delocalization error 69 in the approximate density functionals which artificially stabilizes crystal structures containing more planar conformations of ROY that exhibit greater π conjugation. 29,55,70,71 Delocalization error also can cause overbinding of halogen-bonded crystals 72 and even spurious proton transfer in acid-base co-crystals due to artificial stabilization of salt forms over the neutral co-crystal. 73 We previously demonstrated that the stability rankings of the major experimentallyknown polymorphs in ROY and a number of other systems improve dramatically if one corrects the intramolecular conformational energies using an electronic structure model that does not suffer from delocalization error.…”

“…73 We previously demonstrated that the stability rankings of the major experimentallyknown polymorphs in ROY and a number of other systems improve dramatically if one corrects the intramolecular conformational energies using an electronic structure model that does not suffer from delocalization error. 71,74,75 Whereas the ROY studies of the impact of delocalization error described above considered only experimentally-known polymorphs, the present study now performs crystal structure prediction and applies our conformational energy correction approach to investigate the landscape containing all experimentally-known polymorphs of ROY and hundreds of additional candidate structures. This effort results in the first ROY crystal energy landscape that is highly consistent with experiment.…”

Fast and Accurate Electric Field Gradient Calculations in Molecular Solids With Density Functional Theory

“…In addition to improving the accuracy of CS tensor predictions, monomer correction methods have proven successful in modeling the energetics of conformational polymorphs (Greenwell and Beran, 2020). Here we extend the GIPAW + MC model to EFG tensor calculations and apply GIPAW + MC tensor calculations to a benchmark set of 22 molecular crystals with a total of 46 unique 17 O environments.…”