Molecular crystal structure prediction is increasingly being applied to study the solid form landscapes of larger, more flexible pharmaceutical molecules. Despite many successes in crystal structure prediction, van der Waals-inclusive density functional theory (DFT) methods exhibit serious failures predicting the polymorph stabilities for a number of systems exhibiting conformational polymorphism, where changes in intramolecular conformation lead to different intermolecular crystal packings. Here, the stabilities of the conformational polymorphs of o -acetamidobenzamide, ROY, and oxalyl dihydrazide are examined in detail. DFT functionals that have previously been very successful in crystal structure prediction perform poorly in all three systems, due primarily to the poor intramolecular conformational energies, but also due to the intermolecular description in oxalyl dihydrazide. In all three cases, a fragment-based dispersion-corrected second-order Møller–Plesset perturbation theory (MP2D) treatment of the crystals overcomes these difficulties and predicts conformational polymorph stabilities in good agreement with experiment. These results highlight the need for methods which go beyond current-generation DFT functionals to make crystal polymorph stability predictions truly reliable.
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How many more polymorphs of ROY remain undiscovered
With 12 crystal forms, 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecabonitrile (a.k.a. ROY) holds the current record for the largest number of fully characterized organic crystal polymorphs. Four of these polymorph structures have been reported since 2019, raising the question of how many more ROY polymorphs await future discovery. Employing crystal structure prediction and accurate energy rankings derived from conformational energy-corrected density functional theory, this study presents the first crystal energy landscape for ROY that agrees well with experiment. The lattice energies suggest that the seven most stable ROY polymorphs (and nine of the twelve lowest-energy forms) on the Z′ = 1 landscape have already been discovered experimentally. Discovering any new polymorphs at ambient pressure will likely require specialized crystallization techniques capable of trapping metastable forms. At pressures above 10 GPa, however, a new crystal form is predicted to become enthalpically more stable than all known polymorphs, suggesting that further high-pressure experiments on ROY may be warranted. This work highlights the value of high-accuracy crystal structure prediction for solid-form screening and demonstrates how pragmatic conformational energy corrections can overcome the limitations of conventional density functionals for conformational polymorphs.
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- Award ID(s):
- 1955554
- NSF-PAR ID:
- 10335045
- Date Published:
- Journal Name:
- Chemical Science
- Volume:
- 13
- Issue:
- 5
- ISSN:
- 2041-6520
- Page Range / eLocation ID:
- 1288 to 1297
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/d1sc06074k
