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Electron diffraction opens new possibilities for structure-based drug discovery

Author: Guillaume Jung, with contribution of Dr. Tim Grüne, Villigen
Visualization of hydrogen atoms can be refined against electron diffraction data. From left to right: field of view: 3μm, crystal 1.6μm~400nm; diffraction pattern, dmin < 0.8Å; visualisation of hydrogen atom positions (encircled)
Visualization of hydrogen atoms can be refined against electron diffraction data. From left to right: field of view: 3μm, crystal 1.6μm~400nm; diffraction pattern, dmin < 0.8Å; visualisation of hydrogen atom positions (encircled)

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Modern pharmaceutical development is tailored to the chemical and physical characteristics of active organic compounds. The reason why the atomic structure of pharmaceutical compounds is so important is that most molecules can exist in multiple form variations, called polymorphs. Each polymorph might have different physiological effects: some can be active substance, other completely inactive or worst have negative side effects. Obtaining a polymorph portfolio of a pharmaceutical compound is a demanding process requiring novel analytical methods. But its importance is not to be underestimated as it helps design a safe and effective medicine.

There are two commonly used methods to determine polymorphic structures: single-crystal (SC-XRD) and powder X-ray diffraction (XRPD). Both use X-ray beams to analyze the sample, be it a single crystal or powder formed of multiple nanocrystals. Because the crystals are formed by periodical arrangements of identical building blocks, they act like multi-mirror objects and deviate parts of the X-ray beam in different direction creating a specific diffraction pattern. The respective position and intensity of the diffraction spots are collected and analyzed to determine the structure of a molecule that had formed the crystals building blocks.

For crystals of 10 µm (micrometer) or larger, single-crystal X-ray diffraction is suitable. However, X-ray damage becomes an issue for smaller crystals. In this case X-ray powder diffraction is the preferred method. And yet, since the signal of a large number of crystals is averaged, the signal of individual nanocrystals can be lost. Thus, despite its advantages, X-ray powder diffraction may fail to detect one or more polymorphic modifications associated only with nanocrystals, especially if they are present in small amounts, e.g. less than 1–5 wt% (percentage by weight).

Fascinating alternative to X-ray diffraction

Both methods are constantly evolving, in XRPD new lowest limits of detection are achieved and SC-XRD allows the identification of an absolute structure. However, to meet the scientific and industrial need, new complementary methods, such as Electron Diffraction (ED) come to life. Applied in the nano range, where conventional X-ray methods are not sensible enough, electrons on the other side have perfect properties to allow diffraction and structure determination for individual nanocrystals. Using a standard transmission electron microscope, electron diffraction can reveal the structure of any individual nanocrystal and open a large field of new possibilities. To illustrate the gap between micro and nanocrystal and thus better understand what opportunities this new technology provides, one should imaging a vessel with one cubic meter of water in it and another one with only a few droplets.

The possibility to determine a structure from powders with only very few nanocrystals carries at least two important advantages. Firstly, it produces reliable data and structures that cannot be determined and validated with established methods from the well matured field of X–ray crystallography. Secondly and more importantly, data collection from nanocrystals provides information from samples that have failed X–ray diffraction because of too small or too few crystals. Thus, a lot of time in sample preparation can be saved. In combination with powder diffraction, electron crystallography can sometimes distinguish between intrinsic disorder and samples composed of several types of crystals, which is important, e.g. for the purity and thus efficiency of drugs.

To illustrate the potential market for electron diffraction: Novartis has a library of 2 million compounds, 30-40% of them have been crystallized as powders but only 10% are available as single crystals. (source: Dr. Trixie Wagner (2012)). This means that electron diffraction expands the possibility of single crystal structure determination from the macroscopic world into the nano world and potentially multiplies the number of accessible structures by a factor of three to four! It is tremendous step forward for pharmaceutical, agro-chemical and other industries.

Read more about the potential of electron diffraction

How can this novel method complement well established field of X–ray crystallography? What are the hardels on its way to industry and how can companies benefit from the data it provides? Download the complete article for free and find out more.