Enhanced NMR Discrimination of Pharmaceutically Relevant Molecular Crystal Forms through Fragment-Based Ab Initio Chemical Shift Predictions.

Joshua D Hartman,Graeme M Day,Gregory J O Beran

doi:10.1021/acs.cgd.6b01157

Abstract

Chemical shift prediction plays an important role in the determination or validation of crystal structures with solid-state nuclear magnetic resonance (NMR) spectroscopy. One of the fundamental theoretical challenges lies in discriminating variations in chemical shifts resulting from different crystallographic environments. Fragment-based electronic structure methods provide an alternative to the widely used plane wave gauge-including projector augmented wave (GIPAW) density functional technique for chemical shift prediction. Fragment methods allow hybrid density functionals to be employed routinely in chemical shift prediction, and we have recently demonstrated appreciable improvements in the accuracy of the predicted shifts when using the hybrid PBE0 functional instead of generalized gradient approximation (GGA) functionals like PBE. Here, we investigate the solid-state 13C and 15N NMR spectra for multiple crystal forms of acetaminophen, phenobarbital, and testosterone. We demonstrate that the use of the hybrid density functional instead of a GGA provides both higher accuracy in the chemical shifts and increased discrimination among the different crystallographic environments. Finally, these results also provide compelling evidence for the transferability of the linear regression parameters mapping predicted chemical shieldings to chemical shifts that were derived in an earlier study.

Highlights

Molecular crystal structure is governed by a delicate balance among intra- and intermolecular interactions, and even small changes in the crystallization process may lead to different crystal packing motifs, or polymorphs
While single-crystal and powder X-ray diffraction remain the primary methods for crystal structure determination and fingerprinting solid forms, solid-state nuclear magnetic resonance (NMR) is an increasingly used alternative
NMR chemical shielding is a function of the local electronic structure, making it sensitive to both the molecular geometry and local crystallographic environment, and is an excellent tool for investigating polymorphism

Summary

■ INTRODUCTION

Molecular crystal structure is governed by a delicate balance among intra- and intermolecular interactions, and even small changes in the crystallization process may lead to different crystal packing motifs, or polymorphs. Benchmark studies on many different molecular crystals have demonstrated that, for a given density functional, the inexpensive two-body fragment model predicts 1H, 13C, and 15N chemical shifts on par with the cluster, cluster/fragment, and GIPAW approaches.[55,78,79] For 17O, many-body effects are more important, and cluster-type and GIPAW models perform moderately better than the fragment approach. The differences among χ2 values computed with a given method for different shift assignments indicate the ability of that method to discriminate between correct and incorrect assignments This is an important consideration when using NMR for validation of proposed crystal structures. These differences in χ2 will be the primary focus of the discussion of the results

■ RESULTS AND DISCUSSION

Combined Set

■ ACKNOWLEDGMENTS

■ REFERENCES