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

Gregory J. O. Beran,Qun Zeng,Bochen Li,Guangxu Sun,Chandler Greenwell,Shuhao Wen,Peiyu Zhang,Jessica L. McKinley

doi:10.1039/c9sc05689k

Gregory J. O. Beran, Qun Zeng + Show 6 more

Open Access

https://doi.org/10.1039/c9sc05689k

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Abstract

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.

Highlights

Crystal packing in uences the physical properties of organic crystals
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
While periodic DFT models may have reduced the prevalence of such balance issues compared to earlier force eld studies, the results here clearly demonstrate that widely used density functionals have not yet solved the problem of ranking conformational polymorphs in crystal structure prediction

Summary

Introduction

Crystal packing in uences the physical properties of organic crystals. The occurrence of multiple crystalline packing motifs, or polymorphs, of a pharmaceutical can impact its solubility, bioavailability, shelf-life/stability, and tabletting properties, for example. The present study examines three challenging cases of conformational polymorphism in detail: ortho-acetamidobenzamide,[40] ROY,[42,86] and oxalyl dihydrazide (Fig. 1).[40,87] It demonstrates how problems in the intramolecular conformational energies and, to a lesser extent, the intermolecular interactions with well-regarded dispersion-corrected DFT functionals lead to incorrect polymorph stabilities Modeling these systems with fragment-based correlated wavefunction methods overcomes these difficulties, restoring the crucial balance between intra- and intermolecular interactions[88,89,90] that is required to predict the correct stabilities in conformational polymorphs. The results here highlight how despite considerable progress with DFT, polymorph stability ranking remains challenging, and models that can achieve higher accuracy than that of commonly used DFT approximations are needed before polymorph ranking can be considered a “solved” problem

Theory and methods

Results and discussion

Method

Oxalyl dihydrazide

Findings

Conclusions