NMR Crystallography from Protons – NMR-X

The aim of this project is to provide a robust tool for the atomic structure determination of complex molecular powders at natural isotopic abundance by developing the state-of-the-art in solid-state NMR crystallography using proton spectroscopy. This project addresses two of the fundamental barriers to widespread application of this technique. First, we aim to increase the range of compounds that can be studied by improving the resolution of proton solid-state NMR spectroscopy via the design and implementation of optimized decoupling pulse sequences. Second, we aim to (i) remove barriers caused by a current poor understanding of spin diffusion dynamics in relation to atomic coordinates by developing a better understanding of proton spin-diffusion through a combination of numerical simulation and experiment in order to allow the extraction of reliable structural information from proton spin-diffusion curves, and (ii) remove the need for spin diffusion entirely by developing a chemical shift only protocol.

Both goals correspond to challenges at the very forefront of international research.

The advances gained in these key areas will then be put to use through the demonstration of the applicability in two key pharmaceutical applications: (i) fast identification of polymorph mixtures, and (ii) structure determination of larger drug molecules, with what would be today the first ever complete structure of a molecular organic powder of previously unknown structure by NMR at natural abundance.

The most impressive result obtained so far is the possibility to determine the structures of large drug molecules in powder form, using only 1H NMR chemical shifts in combination with advanced structure prediction methods and plane-wave DFT calciulations, as exemplified by Cocaine free base. We demonstrate how to do this in the publication “Powder Crystallography of Pharmaceutical Materials by Combined Crystal Structure Prediction and Solid-State 1H NMR Spectroscopy,” in Phys. Chem. Chem. Phys. 15, 8069 (2013).”

Our proposed project addresses the current barriers to widespread application of NMR crystallography to complex powders. Recent developments in the Lyon laboratory, combined with the novel ideas contained in this proposal, are expected to lead to breakthroughs in all these areas, such that a robust and versatile powder crystallography tool using solid-state NMR with proton-spin-diffusion will result. The development of such a tool will have a significant and immediate impact on applications relating to pharmaceuticals and new materials, which cannot currently be characterized by any method at the atomic level. This tool will be of widespread use to the materials science and pharmaceutical communities, both academic and industrial, throughout the world.

The work has been presented at several international conférence, in the USA, Ireland, Sweden, India and elsewhere.

The work has so far led to six publications, one on how to predict the diffusion of spin polarisation in a solid based on the structure, a problem at the heart of this project : J.-N. Dumez, M.E. Halse, M.C. Butler and L. Emsley, “A First-principles description of proton-driven spin diffusion,” Phys. Chem. Chem. Phys. 14, 86 (2012).

A second paper describes an important step towards improving the resolution of the measurements that are used to determine crystal structures: M.E. Halse and L. Emsley, “A common theory for phase-modulated homonuclear decoupling in solid-state NMR,” Phys. Chem. Chem. Phys. 25, 9121 (2012).

A third paper demonstrates how to determine the structures of large drug molecules in powder form, exemplified by Cocaine free base, “Powder Crystallography of Pharmaceutical Materials by Combined Crystal Structure Prediction and Solid-State 1H NMR Spectroscopy,” in Phys. Chem. Chem. Phys. 15, 8069 (2013).”

The ability to determine three-dimensional molecular structures from single crystals by diffraction methods (either using x-rays or neutrons) has transformed molecular and materials science over the past 50 years, leading to today’s structure based understanding of Chemistry and Biochemistry. Current state-of-the-art diffraction methods can characterize a wide range of systems such as membrane proteins, whole virus particles, super-molecular nanostructures, complex inorganic materials or even transient time-resolved structures. However, if the system under investigation exists in the form of a powder, either naturally due to the preparation of the substance, such as in the case of many pharmaceuticals, or because large enough crystals for diffraction are unobtainable, the problem of structure elucidation becomes much more challenging. Due to the increasing frequency with which such samples are encountered, particularly in the area of new materials, the development of new methods for structure characterization of powder samples is an area of great current interest and the subject of ongoing research.

Recent advances in powder crystallography have been made using both powder x-ray (or neutron) diffraction methods and solid-state nuclear magnetic resonance (NMR). The research group at the host institution in Lyon is the world leader in developing NMR crystallography of molecular powders, having published the only two full ab initio atomic structures of molecular powders determined by NMR at natural abundance, to date. Their recently introduced NMR crystallography approach combines proton spin-diffusion (PSD) solid-state NMR experiments with computational techniques to obtain complete ab initio structure determination of powdered solids at natural abundance.

This result was achieved in the context of a previous ANR project. Indeed, the project proposed here follows on from the ANR Blanc 2006 project “PSD-NMR” (ANR-06-BLAN-0390). The key result was the development of a full protocol for powder NMR structure determination. This is a veritable turning point for solid-state NMR, and opens up a multitude of possibilities for future research.

Application of this technique to complex molecules and materials of relevance to pharmaceuticals and other applications is limited by the resolution of proton solid-state NMR spectra and by the poorly understood phenomenological model of proton spin-diffusion.

In this project we will address the key remaining bottlenecks to powder NMR crystallography of molecular solids, which can be highlighted in the context of the protocol developed in the previous project and shown in the figure. These are essentially to increase the resolution in 1H spectra and to improve the model used in the “structure determination” step.

In this project we thus seek to improve the overall performance of NMR crystallography specifically (i) by improving the resolution of proton solid-state NMR spectroscopy using optimized homonuclear decoupling pulse sequences, (ii) by developing a better understanding of spin- diffusion, (iii) by discovering methods that only use chemical shifts and (iv) by developing new applications to large organic pharmaceutically related molecules.

This project involves several groups across Europe, including collaborations between the Lyon group and other European scientists including, C.J. Pickard (UC London), G. Day (Cambridge, UK), R.K. Harris (Durham, UK), S.P. Brown (Warwick, UK), and A.M. Gil (Aveiro, Portugal). This group will play an important role in the success of this project. The collaborative and interdisciplinary nature of this work is a perfect example of a joint effort to push forward the frontiers of science and our understanding of nature.

In addition to scientific collaborations, this project also provides opportunities for collaborations with European industrial partners, in particular within the Pharmaceutical industry.