Structure Determination by Powder NMR Crystallography

The inability to determine molecular structures from powdered samples is a key barrier to progress in many areas of molecular and materials science. The main goal of this proposal is to develop a method to determine structures of complex chemical compounds in powder form (e.g. pharmaceuticals) and at natural isotope abundance by nuclear magnetic resonance (NMR) crystallography, which has been introduced and pioneered by the host research group in Lyon. They have recently published the first full protocol for molecular structure determination from NMR spectra of powder samples at natural abundance. This approach combines proton spin-diffusion (PSD) solid- state NMR experiments with computational techniques to achieve complete ab initio structure determination of powdered solids at natural abundance. This represents a veritable turning point for solid-state NMR, and opens up a multitude of possibilities for future research. Application of PSD based NMR crystallography to complex chemical compounds and to materials of relevance to pharmaceuticals and other molecules of interest is currently limited by the resolution of proton solid-state NMR spectra and by the insufficient current mostly phenomenological model of proton spin-diffusion. The proposed research project addresses these remaining key bottlenecks and will strive to improve the overall performance of NMR crystallography, specifically (i) by increasing the resolution of proton solid-state NMR spectra using optimized homonuclear decoupling pulse sequences, (ii) by introducing methods that rely exclusively on chemical shift values and (iii) by developing new applications suitable for large organic compounds. The practical applicability of the advances achieved in these key areas will then be demonstrated in two key pharmaceutical applications: (i) fast identification of polymorph mixtures, and (ii) structure determination of larger drug molecules, with what as of today would the first ever complete previously unknown organic molecular structure determined from a powder sample by NMR at natural isotope abundance. Such a successful demonstration will tremendously impact the protocols of organic and biomolecular structure analysis used in academic and industrial laboratories.