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Microfabricated resolution targets for pharmaceutical imaging Most people take medicine with only the end result in mindOfor example, relief from a killer headache. What they might not realize is that ordinary-looking tablets are actually marvels of engineering design. In recent years, advanced analytical techniques, such as Raman chemical imaging, have allowed researchers to characterize quantitatively the physical and chemical properties of medications in exquisite detail. However, the application of such techniques to pharmaceutical products often requires modification of existing instrumentation and standards. To better understand the usefulness and limitations of Raman chemical imaging of pharmaceutical materials, John F. Kauffman and colleagues at the U.S. Food and Drug Administration (FDA) and Saint Louis University fabricated polyethylene glycol (PEG)-on-silicon resolution targets to gauge the accuracy of measurements; the researchers present their work in a new AC paper (DOI 10.1021/ ac800864x). Raman chemical imaging combines microscopy with Raman spectroscopy to produce a spectral image that can indicate the chemical composition of a material. Kauffman and co-workers had tried to use Raman chemical imaging to map the thickness of a coating over the entire surface of a tablet. (Small cracks or thin spots in the coating might alter the release profile of the drug and therefore reduce efficacy.) “The results we obtained didn’t really make sense,” says Kauffman. “This led us to explore a phenomenon known as subsurface scattering and its effect on resolution.” Subsurface scattering occurs when the light source for Raman spectroscopy penetrates a nonopaque particulate material, such as a pharmaceutical compound, and is scattered not only by the particles on the surface but also by those particles beneath the surface of the imaged object. Kauffman’s team wanted to quantitate the reduction in spatial resolution caused by subsurface scattering. 5676
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In Raman chemical imaging, the accuracy of an image typically is estimated with resolution targetsOtiny strips of metal of known widths on glass slides. These metal-on-glass targets work well for determining the resolution of images of opaque inorganic or metallic materials such as semiconductors. But according to Kauffman, “Metal-on-glass resolution targets don’t behave anything like pharmaceutical materials because light doesn’t penetrate the metal. The signal arises primarily from the surface, and diffuse scattering is minimal.”
Composite Raman chemical image of polymorphic acetaminophen crystals, in which the two forms can be distinguished by different colors (red or blue).
To produce a more suitable resolution target for the chemical imaging of pharmaceutical compounds, the investigators fabricated a PEG-on-silicon device by using the micromolding in capillaries (MiMIC) method. PEG is a nonopaque, polycrystalline, organic compound that undergoes subsurface scattering and therefore mimics the behavior of typical pharmaceutical materials. Kauffman and colleagues made a reusable plasma desorption MS mold with ⬃10-m-deep channels of various widths (5⫺25 m), sealed the mold to a silicon substrate, and filled the mold
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with melted PEG powder. After cooling, the mold was removed to reveal highly reproducible, thick, parallel lines of solid PEG on the silicon substrate. The researchers compared the impulse-response functions of the PEG-onsilicon and conventional metal-on-glass resolution targets. The impulse-response function characterizes the instrument’s distortion of the true shape of an object. Impulse-response functions can be compared quantitatively by measuring the width of the impulse-function line shape at half the maximum height: the greater the impulse width, the lower the resolution of the instrument. Kauffman and colleagues found that the PEG-on-silicon resolution targets had ⬃2-fold greater impulse widths than the PEGon-metal targets did. This result suggests that because of subsurface scattering, Raman chemical images of nonopaque substances such as pharmaceutical compounds have ⬃2-fold lower resolution than images of opaque materials such as metals have. Because the fabrication of PEG-onsilicon resolution targets by the MiMIC process is highly reproducible, the targets could prove useful for the standardization of Raman chemical imaging data among laboratories. In addition, it might be possible to derive algorithms to correct the image distortion. “Our main interest lies in understanding the limitations of the instrument,” says Kauffman. “If a sponsor of a drug application submits data from a Raman imaging system, we [the FDA] would like to be able to understand the factors that influence the spatial resolution of the instrument so that we can make an informed assessment of the data.” —Laura Cassiday
10.1021/AC801290A 2008 AMERICAN CHEMICAL SOCIETY
Published on Web 07/31/2008
