X-ray Microtomography of Solid Dosage Forms

Pharmaceutical scientists have long sought the ability to see inside the solid dosage forms they produce to determine their products' structural features and to better understand their mode of action. Previous studies have used various techniques for visualizing the internal structure of solid dosage forms, including 1H NMR imaging (1), confocal microscopy (2), and conventional microscopy (optical and electron) combined with mechanical slicing of samples (i.e., microtoming) (3). One drawback of several current techniques is their invasive nature that can destroy the sample and prevent any further testing. Another is the techniques' limited penetration and resolution. Thus, it is probably fair to say that the ideal experimental approach for the three-dimensional structural imaging of pharmaceutical dosage forms has not yet been realized.

Figure 1: Schematic of X-ray microtomography instrument (I0 = incident beam, ItMay In the Field section5 = transmitted beam).
X-ray microtomography is a relatively new approach to imaging the internal structure of solid dosage forms. This technique has been widely used for the in vivo imaging of plants, insects, animals, and humans. X-ray microtomography is a nondestructive technique that has a high penetration ability and provides a reasonable level of resolution (~5–20 μm).

Figure 2: Conventional bilayer tablet structure.
Principles of X-ray microtomography The X-ray microtomography approach used in this work is an extension of the computer aided tomography (CAT) medical imaging technique commonly used in hospitals. X-rays are directed from a high-power source toward a sample, and a detector on the opposite side of the sample measures the intensity of the transmitted X-rays (see Figure 1). A two-dimensional "shadow" image is produced by accurately rastering the X-ray beam across the sample. The sample then is carefully moved (usually rotated) relative to the X-ray beam, and the process is repeated to produce additional two-dimensional images from various view points. Using a sophisticated Fourier transform algorithm, the two-dimensional images then are combined to generate a complete three-dimensional map of the sample.

Figure 3: Cross section of a fast-dissolving tablet manufactured by lyophilization.
The intensity of the X-rays reaching the detector is controlled by the sample path length and the X-ray attenuation coefficient of the material that it encounters on that path (4). The longer the path length and the greater the attenuation coefficient of the material (see http://physics.nist.gov/PhysRefData/XrayMassCoef/tab3.html ), the greater the number of diffraction and scattering events, thereby weakening the X-ray beam that reaches the detector. The varying levels of signal intensity provide a gray-scale in the images from which information about the density, thickness, and attenuation properties of the sample can be obtained. Very dense or thick regions and areas that contain heavy elements (e.g., sodium, chlorine, or iron) will generally create the most contrast in the final images. In very simple terms, X-ray microtomography can be thought of as creating a three-dimensional map of the relative atomic density of the sample under evaluation.