The majority of crystal structure prediction (CSP) studies generate structures that are more thermodynamically stable than some observed polymorphs, raising the question of why we do not observe more polymorphs.Sometimes, this is because the right experiment has not yet been done, and a non-routine experiment can be designed from the computer-generated structure and its physical properties, which finds the new polymorph. This has been done by subliming onto a template crystal, or crystallising under pressure or in a strong magnetic field. However, some structures are artefacts of the static crystal modelling used in CSP. Performing Molecular Dynamics simulations can show that groups of CSP structures cannot be distinguished when the dynamic motion of molecules in the crystals is taken into account, thus reducing the number of unobserved thermodynamically competitive structures. Such simulations are sensitive to the realism of the entire potential energy surface, and so there is a challenge in determining a force-field that will realistically model cases where the transformation to more stable structures is so facile that the intermediate structures cannot be observed. There are cases of irreproducible polymorphs that challenge methods of determining which CSP generated structures can be observed. Current lattice energy based CSP methods are just a zeroth-order approximation to predicting how an organic molecule can crystallize, which could be made more useful if systematically enhanced with Molecular Dynamics screening approaches.

Can we distinguish between CSP-generated structures that could be found and those that could never be found?

ACS Spring Meeting 2021

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