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Analytical Chemistry

Solving Powder Structures

Spectroscopy: Computational NMR approach deciphers what other methods cannot

by Jyllian Kemsley
November 11, 2013 | A version of this story appeared in Volume 91, Issue 45

Credit: J. Am. Chem. Soc.
The crystal structure of AZD8329 form 4 was determined using solid-state NMR.
Crystal structure of 4-[4-(2-adamantylcarbamoyl)-5-ter-butyl-pyrazol-1-yl] benzoic acid, aka AZD8329, a type 2 diabetes drug candidate.
Credit: J. Am. Chem. Soc.
The crystal structure of AZD8329 form 4 was determined using solid-state NMR.

Molecules can crystallize in different forms, which may have variable stability or solubility properties. For materials and pharmaceutical applications that use microcrystalline powders, manufacturers must be able to reliably produce specific crystal forms and have analytical methods available to ensure that they’re doing so.

But such testing is easier said than done. “Solving structures of molecular solids from powder diffraction data is highly challenging, and complementary techniques are desperately needed,” comments Paul Hodgkinson, a chemist at England’s Durham University.

By combining computational work and solid-state nuclear magnetic resonance spectroscopy (NMR), an international team of researchers has pioneered a technique to solve the crystal structure of a small molecule (J. Am. Chem. Soc. 2013, DOI: 10.1021/ja4088874).

The new approach improves on solid-state NMR techniques for determining three-dimensional structures, in large part by sidestepping the need for isotopic labeling of samples.

The team was led by Lyndon Emsley, a chemist at France’s University of Lyon and scientific director of the Lyon-based European Center for High-Field NMR, and Graeme M. Day, a chemist at the University of Southampton, in England.

Their technique includes three parts. First, they use computational analysis to develop a set of possible crystal structures of a molecule based on its chemical structure. Then they calculate the 1H NMR chemical shifts each crystal structure would show. Finally, they match the calculated chemical shifts to the experimental spectrum obtained from the powder.

The team reporting the new work analyzed an AstraZeneca drug candidate for type 2 diabetes called AZD8329. The drug has seven known crystal forms; AstraZeneca chose two for development on the basis of their material properties. One of the two, “form 4,” had not been structurally characterized. The Emsley-Day team used its new approach to identify 34 crystal structure candidates computationally—one of the structures exhibited a calculated spectrum that matched that of the form 4 powder.



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