Patents III. Examples of the Use of Powder Diffractions in Patents

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Examples of the Use of Powder Diffractions in Patents

Aspartame (tradename NutraSweet)

Background
Aspartame is one of the safest and best selling artificial sweeteners. It was discovered by a company in the Monsanto group and G.D. Searle marketed it as NutraSweet. They now sell many thousands of tonnes per annum. At first there were no table-top tablet aspartame products, because the crystalline form used was too hygroscopic. However, Pepsi and Coca-Cola both decided to use NutraSweet in their diet products at around the same time, and there was an enormous surge in demand. Aspartame is a α-L-Aspartyl-L-phenylalanine methyl ester, the methyl salt of a dipeptide of two natural amino acids.

The Case
The main litigation involved only one of the four or so pseudo-polymorphs (different ratios of water of crystallization), of the hemihydrate. For this crystalline hemihydrate Ajinomoto had discovered a process which made much larger crystals, which were more perfect, less hygroscopic and more stable. This is detailed in, for instance, European Patent 0 119 837 "Dipeptide crystals, a process for their production, tablets containing the dipeptide crystals and a process for the production thereof." These became known as "bundle" crystals of the hemihydrate, because of their outward appearance. They were produced, surprisingly, from a non-stirring batch process, and Ajinomoto argued that this process was novel, not obvious and clearly had industrial application. Various others suggested that larger crystals were obvious, even 100,000 times larger.

The Crystallography and Powder Diffraction
Once larger and more perfect crystals became available, it was possible to determine the crystal structure by x-ray diffraction, and by the time Ajinomoto's process reached the European patent courts there was a published structure for these 'bundled' crystals (J. Am. Chem. Soc., 107, 4279 - 4282, (1985) "Crystal Structure of Aspartame, a Peptide Sweetener" by Hatada et al). Ajinomoto set out to show that the "bundle-like" and "conventional" crystals were radically different and used a battery of methods, including crystallographic techniques such as polarising light microscopy, some single-crystal work, structure simulation and SEM in combination, but one of the most vital clues came from the powder diffraction data.

Using SEM, single-crystal Weissenberg and habit modelling we were able to determine the preferred orientation, particularly for the large bundle-like crystals and estimate the size of the small state of the art conventional crystals. Then taking the crystal structure data from the published structure and adding to that the preferred orientation and size/strain effects the powder diffraction patterns were simulated of both the bundle-like and the conventional crystals and show a good comparison with the collected data. This showed that although the two types of crystals were based on the same structure there was clearly large disorder in the small crystals (which have broader diffraction peaks) and in contrast far greater perfection in the larger crystals, but also a strong preferred orientation. X-ray powder diffraction patterns of various forms were included in the 0 119 837 patent, but not a good comparison of the two types of hemi-hydrate crystal.

A Further Example of Complex Powder Diffraction in Patents: Magnesium Hydroxide Fire Retardant

Magnesium hydroxide is a good flame retardant material for thermoplastics, etc., (for instance in the coverings of cables for fire alarm systems), but fine powders tend to aggregate and not disperse in resins. Finer, more easily dispersed powders are the subject of many patents (search on magnesium hydroxide in any of the patent databases in the links page for instance) and a previous UK patent 1,514,081 seeks to patent a form of magnesium hydroxide with 'markedly small strain in the <101> direction, a large crystallite size in the same direction ..." and of course uses powder diffraction to establish this, including not only a methodology for measuring size/strain from the (101) and (202) peaks but also a description of the diffractometer settings and calibration graphs.

Powder diffraction, whilst mainly used just to identify the crystalline phase being patented, is also used in many other forms in patent work, including quantitative analyses. In the establishment of patents on particular compounds, powder diffraction can play a particularly important in cases where the substance in question shows polymorphism, i.e. it can crystallise in more than one form.

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