Overcoming the difficulties of predicting conformational polymorph energetics in molecular crystals via correlated...

Area of Science:

• Solid-state chemistry
• Computational chemistry
• Crystallography

Background:

• Molecular crystal structure prediction is vital for pharmaceuticals.
• Current density functional theory (DFT) methods fail for conformational polymorphism.
• Conformational polymorphism arises from intramolecular changes affecting crystal packing.

Purpose of the Study:

• To evaluate DFT performance in predicting conformational polymorph stabilities.
• To investigate the accuracy of fragment-based MP2D methods for these systems.
• To identify reliable methods for crystal structure prediction of flexible molecules.

Main Methods:

• Examined conformational polymorph stabilities of o-acetamidobenzamide, ROY, and oxalyl dihydrazide.
• Assessed performance of van der Waals-inclusive DFT functionals.
• Applied fragment-based dispersion-corrected second-order Møller-Plesset perturbation theory (MP2D).

Main Results:

• Standard DFT functionals showed significant failures in predicting polymorph stabilities.
• Failures were attributed to inaccurate intramolecular conformational energies and intermolecular descriptions.
• MP2D treatment successfully predicted conformational polymorph stabilities for all tested systems.
• MP2D results showed good agreement with experimental data.

Conclusions:

• Current DFT functionals are inadequate for reliable crystal polymorph stability prediction of flexible molecules.
• Fragment-based MP2D offers a more accurate approach for these challenging systems.
• Advanced computational methods are necessary for dependable crystal structure prediction in pharmaceutical research.