A blind test of crystal-structure prediction technology is organized every two to three years by the Cambridge Crystallographic
Data Center. The latest results of the 2007 blind test show that the approach championed by M. Neumann in cooperation with
F. Leusen and J. Kendrick from the Institute of Pharmaceutical Innovation at the University of Bradford (Bradford, UK), which
generated and optimized the crystal structures using the quantum mechanics-derived forcefields followed by final energy ranking
using the d-DFT calculations, allows for the accuracy required (9, 10). In this latest blind test, they were the only group
out of 14 participants to predict all four challenges correctly.
Avantium Pharma recently started to offer computational polymorph prediction services in collaboration with Avant-garde Materials
Simulation. The computational results can be used for various purposes: a confirmation of experimental results, as a guide
during experimental screening, and to understand the crystal structures of the polymorphic forms generated. This is the first
time that the field of crystal-structure prediction has advanced enough to apply the technology to pharmaceutically relevant
molecules. Multiple component crystals (hydrates, solvates, and cocrystals) can be handled as well.
All these efforts are geared toward the reduction of the risk that pharma companies run during drug development: when you
know which the most stable structure is, you know what to look for in the experimental screening for polymorphs, and you will
also know when to stop searching. You can also assess the likelihood of a competitor finding a developable metastable form
and protect your intellectual property before this happens.
Chiral APIs and hydrated compounds
» Can you outline some recent advances in X-ray crystallography in use for certain types of APIs?
One of the key regulatory requirements for a chiral API is proof of absolute stereochemistry. There are several analytical
technologies available for this task; however, the most popular method is that of single-crystal X-ray diffraction. Traditional
crystallography requires single crystals that have dimensions of at least 100 μm in size. For some molecules, it is impossible
to grow crystals this large with sufficiently good quality to determine the crystal structure. Although the newest generation
of single crystal X-ray diffractometers can work with crystals down to about 50 μm, sometimes even with these instruments,
structure and stereochemistry determination is not possible.
In cases such as these, the answer lies in using a synchrotron X-ray facility to provide the radiation source. The flux provided
by a synchrotron is far greater than a standard X-ray source, and thus it can be used to generate diffraction patterns from
much smaller crystals, down to about 5 to 7 μm.
For example, Diamond Light Source's (Didcot, UK) new synchrotron facility has important industrial applications such as determining
absolute stereochemistry of pharmaceutical compounds. [Diamond Light Source is a joint venture funded by the UK government
via the Science and Technology Facilities Council and the Wellcome Trust]. Looking at ~5 μm crystals is at the edge of the capabilities
of even a third-generation synchrotron such as Diamond. The typical experiments carried out there use a shutter speed of 1
s, but to see a diffraction pattern for such a tiny speck of matter, much longer exposures are required, on the order of 10
s per frame. This longer time is because, in general, pharmaceutical molecules are largely made up of lighter atoms (i.e.,
carbon, hydrogen, nitrogen, and oxygen), with the occasional heavier atoms such as fluorine, chlorine, sulfur, or phosphorus.
These lighter atoms have fewer electrons that interact with X-rays to form diffraction patterns.
X-ray crystal structures can also be the only way to determine the connectivity of the crystals, for example, how water of
hydration fits in between the drug molecules. Sodium diclofenac is a good example. Although the drug dates back to the 1960s,
the first crystal structure was solved in 2002, and it suggested that the crystal is a pentahydrate. Yet thermogravimetric
and Karl Fischer analysis consistently suggest 4.83 and 4.69 molecules of water respectively, never 5. By running the experiment
at 120 K, the diffraction patterns are sharper, and it became clear that the ratio of drug molecules to water molecules is
4:19, giving a 4.75 hydrate, which matches up with analytical results. The crystal structure of sodium diclofenac anhydrate
(see Figure 1) was solved for the first time with data collected at the new Diamond synchrotron facility using a needle crystal
of dimensions of 50 X 5 X 3 μm.
Figure 1: View of the anhydrous sodium diclofenac structure down the b-axis of the unit cell. (FIGURE 1 IS COURTESY OF DIAMOND