Will the real structure please step forward

The single-crystal structure of famotidine

The single-crystal structure of famotidine overlaid upon the structure as refined from both neutron and x-ray data simultaneously
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Neutron diffraction has become a powerful technique for obtaining the accurate structure of small organic molecules containing hydrogen.

X-ray diffraction has always been the chemist’s favourite tool for determining the crystal structure of small molecules. However, X-rays cannot easily reveal the true positions of hydrogen atoms in organic materials such as pharmaceuticals. Yet knowing the exact locations and orientations of the hydrogens may be vital in determining how a drug molecule interacts with its target receptor. Furthermore, many such compounds can exist in more than one crystalline form, or polymorph, with relatively weak, so-called hydrogen bonding frequently influencing the way molecules arrange themselves in the crystal. Polymorphs can have markedly differing physical properties, with implications for bioavailability and patenting – issues of great concern to the pharmaceutical industry.
This is where neutron diffraction steps in. Unlike X-rays, neutrons readily scatter off hydrogen atoms to reveal their exact positions; this is particularly advantageous when studying compounds with hydrogen bonding or with disordered hydrogen atoms.
So why have chemists been cautious in using neutrons to study small-molecule crystal structures? One reason is that X-ray diffraction equipment is readily available and structures can be solved relatively quickly, while neutron measurements have always been more time-consuming. Neutron diffraction also requires much larger crystals than its X-ray counterpart – and they may not always be available.
Another issue is that hydrogen atoms generate a lot of background scattering, so are replaced by deuterium where possible to give a better signal. Deuteration works brilliantly for large biological assemblies where the deuterated components can be introduced using biotechnological techniques. However, it may be extremely difficult and expensive to substitute deuterium for hydrogen in small molecules. The presence of heavier deuterium atoms may actually alter the molecular interactions or dynamics in the material.
Thanks to new instrumentation and techniques developed at ISIS, however, these obstacles are being overcome. Larger detector arrays, combined with new data-collection methods – including using multiple crystal samples – and efficient data-processing software, have greatly speeded up the structure determination. 

Look, no deuteration! 

In one recent study, the crystal structure of the anti-ulcer compound famotidine, was determined from a non-deuterated powder sample using both X-rays and neutrons (with the ISIS powder diffractometer GEM). The neutron and X-ray data were used in combination to refine the initial X-ray structure and thus yield a highly accurate final structure. This example aptly shows the tremendous potential of this complementary approach.

Dr Kenneth Shankland, RM Ibberson, WIF David (ISIS) 

Research date: December 2006

Further Information

Single crystal X-ray and neutron powder diffraction investigating of the phase transition in tetrachlorobenzene, SA Barnett et al, Acta Cryst B62 (2006) 287. 

Neutron powder diffraction studies of protonated organic materials, WIF David, K Shankland and RM Ibberson, ISIS Annual Report, 2004. 

Rapid structure determination of the hydrogen-containing compound Cs2C2O4.H2O by joint single-crystal X-ray and powder neutron diffraction, MT Weller, PF Henry and ME Light, Acta Cryst B63 (2007) 426.

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