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Analytical Chemistry

Microscopy technique quickly distinguishes crystal polymorphs

New method may aid drug discovery by speeding up screening process

by Mitch Jacoby
May 10, 2016 | A version of this story appeared in Volume 94, Issue 20

These images are the result of a new microscopy method.
Credit: Garth Simpson/Purdue U.
A new microscopy method generates false color images of microscopic crystals to quickly distinguish between polymorphs. (Monoclinic D-mannitol at left in this example. Orthorhombic, right.)

Pharmaceutical compounds often crystallize in a variety of forms known as polymorphs. Because of differences in stability, solubility, and other properties that affect the molecules’ behavior in the body, one crystal type may lead to a better drug than another. So distinguishing one polymorph from another is crucial to drug development. But the process is time consuming and often requires a substantial sized sample.

A new microscopy method can discriminate between crystal polymorphs in a few seconds by imaging just a few micrograms of a sample, according to a study published in Analytical Chemistry (DOI: 10.1021/acs.analchem.6b00057).

In the search for new pharmaceutical candidates, drugmakers often turn to high-throughput methods to crystallize samples of a given drug candidate. The procedure can quickly produce a large number of samples, enabling researchers to examine how varying synthesis and crystallization conditions may affect a drug’s bioavailability and manufacturability.

To determine that connection, researchers rely on powder X-ray diffraction, Raman and infrared spectroscopy, optical microscopy, and other techniques to assess a sample’s crystal form. Using multiple techniques can create a bottleneck in the screening process and can only be completed if an ample quantity of the sample is available.

To make the process less cumbersome, Purdue University chemists Paul D. Schmitt, Garth J. Simpson, and coworkers devised a laser-driven microscopy technique based on an optical phenomenon called second harmonic generation. This happens when laser light shines on a nonlinear optical material, which includes many pharmaceutical crystals, and the frequency of the light emitted by the material is double that of the incoming light.

The Purdue chemists rapidly modulate the polarization of laser light directed at the sample and then monitor this second harmonic signal, thus allowing them to quickly distinguish crystals on the basis of their structure, symmetry, and other polarization-dependent optical properties.

The team demonstrated the technique by applying it to samples of orthorhombic and monoclinic forms of D-mannitol, which they also analyzed via powder X-ray diffraction. They showed that by using the new method together with a computational algorithm they recently developed, they could discriminate the polymorphs with greater than 99.99% confidence. They could do so with about 1 μg of sample and less than 7 sec of imaging. For comparison, modern benchtop powder X-ray diffraction systems require a minute or longer.

Northwestern University’s Franz M. Geiger, a specialist in similar optical methods, remarks that the new method, “which assesses polymorphism crystal by crystal, with just micrograms of material and in only a few seconds, is an impressive demonstration of the power of nonlinear optics.” This technique will help “put the ‘high’ back into high-throughput screening for polymorph discovery,” he adds.



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