Quantum prediction: polymorphs determined theoretically

Ezine

Published: Mar 15, 2011
Author: David Bradley
Channels: X-ray Spectrometry

thumbnail image: Quantum prediction: polymorphs determined theoretically

Crystal clear predictions

Frank Leusen and his co-workers at the University of Bradford, England, have turned to a quantum mechanical approach to help them predict the three known possible polymorphic structures of a sulfonimide. The work could assist crystallographers in structure determination of unknowns.

For a vast number of crystalline organic compounds there exist two or more polymorphic forms, which means different physical properties and effects depending on application. For materials science this can mean the difference between useful and safe or not. Similarly, for pharmaceutical products, the crystalline form of a drug can strongly influence absorption and efficacy. Until recently, formulation chemists in the pharma industry had no way of determining in advance which polymorphic form of a given product would result from the manufacturing process. But, new theoretical efforts could change that and give chemists the upper hand on crystallisation allowing them to tweak reaction conditions or, moreover, crystallisation conditions to nudge a product towards the desired form.

Structural subtleties

Subtle differences in production conditions, such as variations in pressure, temperature and concentrations, can be enough to cause fine chemicals, such as pharmaceuticals, pigments, explosives, or agrochemicals, to crystallize in a different form. This can lead to problems with the production process or to undesirable product properties.

Of course, the existence of polymorphic forms of many products has given the industry the opportunity to extend patent lifespan on many drugs by formulating the single, most active form. But, conversely, it can lead to costly delays in moving from clinical trials to the market as the profile of an experimentally efficacious compound shifts subtly to the negative once a distinct polymorph emerges at the bulk production scale. There are techniques being developed to help control which polymorph is made during production and supercritical fluids (SCFs) have come to the fore as a useful technology for manipulating a product.

Nevertheless, scientists such as Frank Leusen would prefer to find a way to predict polymorphic structures in advance and so provide an entirely fundamental perspective on the issue. Writing in the journal Angewandte Chemie, the team describes how they have now successfully used a quantum mechanical approach to predict the three crystal structures of a sulfonimide. The presence of the fairly promiscuous sulfur atom in these compounds is one of the chemical issues that gives rise to their ability to crystallise in more than one polymorphic form.

Building on Blind Tests

Previously, Leusen and colleagues have won accolades at the Blind Test in Crystal Structure Prediction, organised by the University of Cambridge and hosted by the Cambridge Crystallographic Data Centre (CCDC). Blind Tests, in 1999, 2001 and 2004 revealed again and again just how difficult crystal structure prediction can be, hit rates were low and no single method consistently proved itself for all types of molecules in the competitions, as SpectroscopyNOW reported. In 2007 as reported in SpectroscopyNOW, Leusen and his co-worker John Kendrick at the University of Bradford in close collaboration with Marcus Neumann at Avant-garde Materials Simulation began to show their predictive prowess and successfully predicted the structures of four "unknowns" using the GRACE software developed by Marcus Neumann.

Computational chemistry methods have been around for many years but accounting for the myriad parameters involved in crystallisation would far exceed today's computational facilities. "Precise, reliable predictions of the crystal structures of organic molecules have remained somewhat of a Holy Grail for crystallography," says Leusen.

Spurred on by their 2007 success with software called GRACE (Generation, Ranking And Characterization Engine), the team has now successfully determined the known structure of a sulphonamide, which was not cracked in the 2001 Blind Test, as well as confirming two additional, previously unknown crystal structures for this compound. "By using the computational process developed by Marcus Neumann at Avant-garde Materials Simulation in Freiburg, Germany, we were able to correctly predict all three crystal structures," says Leusen.

"Even though it is currently not possible to predict the outcome of a specific crystallization experiment under specific boundary conditions," explains Leusen, "our results demonstrate that precise calculations of the lattice energy are sufficient to model crystallization thermodynamics and thus predict the different crystal structures of small organic molecules."

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.