Two back-to-back papers in Angewandte Chemie have potentially serious consequences for one sector of the pharmaceutical industry, as they reveal the inherent ambiguities in the crystalline forms of aspirin.
A team of scientists from Denmark, Germany, and India suggest that the recently reported form II of the ubiquitous pharmaceutical may indeed exist but the crystallographic evidence could just as readily be interpreted as being from a single crystal of form I. The findings could have implications for patent arguments over novel forms of the purportedly generic drug.

Aspirin was first developed from an ancient herbal remedy extract of the willow tree in 1897 and brought to market as the first manufactured pharmaceutical by Bayer. After all these years, one would assume that science had said all that there is to say about the structure and properties of aspirin, but nothing could be further from the truth. New discoveries about this chemical cousin of salicin have shown it not only to be useful in pain and fever relief but also as a novel and simple therapy for stroke and heart disease. As long ago as 1948 Dr Lawrence Craven, a Californian general practitioner was recommending an "aspirin a day" for heart attack prevention.

Cardiovascular patients, particularly in the developed world, represent a fast-growing market for pharmaceutical products, so companies hope to exploit their products to the full. However, should aspirin continue to prove beneficial in treating the after-effects of stroke and heart attack and in preventing their occurrence in the first place, no single company will benefit given aspirin's generic status.

As such, the companies have found several ways to sugar-coat the pill in an effort to create new patentable products. Much of the debate hinges on the existence or otherwise of different polymorphic forms of the drug and whether or not such variations on a single theme might represent novel inventions in the patent lawyers' eyes.

In 2004, computer calculations demonstrated that the well-known crystal structure of aspirin (form I) is the most stable of any that may or may not be present in crystalline aspirin. The same calculations hinted at a second, equally stable form, that would represent a clear challenge for chemists to reconstruct. Matthew Peterson, Michael Zaworotko, and colleagues published details of just such a synthesis of aspirin in form II in 2005. The team obtained this second form by crystallization of pure aspirin in the presence of either levetiracetam (an antiseizure compound) or acetamide from the solvent acetonitrile. They characterized it by single-crystal X-ray diffraction.

In the current Angewandte papers, Andrew Bond (University of Southern Denmark), Roland Boese (University of Essen), and Gautam Desiraju (University of Hyderabad, India) reiterate the structural differences between form I and form II reported by Peterson and Zaworotko but they point out that these differences are rather slight.

More critically, however, the new research suggests that the form II structure "may just as easily be derived, to the accuracy and precision reported by these workers, from experimental diffraction data collected from what is undoubtedly a single crystal of the well-known form I."
Even from the early days of crystal studies into aspirin, there were serious issues surrounding its structure. PJ Wheatley obtained the first crystal structure in 1964, but certainly not without a degree of ambiguity. "After Wheatley, Chick Wilson got very high R-factors in his neutron study of 2000," Desiraju told SpectroscopyNOW.com, "this is what was nagging me throughout, why were these R-factors so high?" Desiraju and his colleagues suggest that the Zaworotko study does not represent much of an improvement on the precision of these earlier studies and moreover confounds attempts to define a new polymorphic form of aspirin.

Both forms, say Desiraju and colleagues, contain pairs of molecules lying in identical layers but these layers are arranged differently in the two different structures. The researchers explain that the ambiguity may have arisen because aspirin has a tendency to crystallize with an unusual intergrown structure. The distribution and ratio of the side-by-side domains are variable but limited. Whereas a pure form I exists, it has so far only been possible to obtain crystals containing a maximum of 85% of form II, they emphasise.

The team is still exploring the reasons for this unusual occurrence but points out that, "the peculiar chemico-legal significance of polymorphism in the pharmaceutical industry today, and the ubiquitous nature of the molecule in question warranted a preliminary publication [of their findings]".

It seems that aspirin represents the first example of a compound that can have two different polymorphic structures in a single crystal. The research up-ends the received wisdom and raises several important questions that will be important not only for crystallographers but also for pharmaceutical patent lawyers. If this is the case for aspirin, what of other compounds? Is such a definition of polymorphism tenable or should it be updated? Let us hope crystallographers get to answer such questions and not lawyers.

Related links:

• J. Chem. Soc., 1964, 6036-6048 (Wheatley et al)
• J. Am. Chem. Soc. 2005, 127, 16802 (Zaworotko et al)
• Angew Chem Int Edn, 2007, 46, a, in press (Desiraju et al)
• Angew Chem Int Edn, 2007, 46, b, in press (Desiraju et al)
• Desiraju Page
• Boese Page
• Bond Page

Article by David Bradley