Discriminating and understanding molecular crystal polymorphism.

Area of Science:

• Solid-state chemistry
• Computational materials science
• Crystallography

Background:

• Polymorph discrimination in molecular crystals is a significant challenge in the pharmaceutical industry.
• Understanding and predicting different crystalline forms (polymorphs) is vital for drug development and manufacturing.

Purpose of the Study:

• To investigate and compare the effectiveness of the eXtended ONIOM method with periodic boundary conditions (XO-PBC) for polymorph discrimination.
• To evaluate the performance of XO-PBC against common dispersion-corrected density functional theory (DFT-D) methods.

Main Methods:

• Energy decomposition analysis based on many-body expansion was employed.
• The XO-PBC method, utilizing XYG3 as the high-level functional and PBE as the low-level functional, was applied.
• Three molecular crystals (tetrolic acid, oxalic acid, oxalyl dihydrazide) exhibiting packing and conformational polymorphism were studied.

Main Results:

• The XO-PBC(XYG3:PBE) method successfully predicted the correct experimental stability orderings for the investigated polymorphs.
• This method also provided reasonable energy ranges for the polymorphs of all three molecular crystals.
• The study highlighted the importance of accurately treating various intermolecular interactions for reliable polymorph prediction.

Conclusions:

• The XO-PBC method demonstrates significant utility and accuracy in polymorph discrimination for molecular crystals.
• Accurate computational treatment of intermolecular interactions is essential for effective polymorph control in the pharmaceutical industry.