The terahertz region of the electromagnetic spectrum lies between 0.06 and 3 THz, which corresponds to 2–100 cm^-1 . It is a region that has been largely ignored by the pharmaceutical industry until recently due to the difficulties of undertaking measurements. These difficulties include the lack of conveniently sized sources and the use of cryogenically cooled detectors. But, recent advances in semiconductors and the availability of robust industrial femtosecond pulsed lasers have resulted in a rapid exploration of terahertz region by the pharmaceutical industry. The new semiconductor sources produce extremely short bursts of terahertz radiation, which are emitted from a point source. These bursts have a broad spectral range that is applicable to spectroscopy. The terahertz region is ideally suited to the investigation of the solid-state properties of pharmaceutical materials. Recent studies have included polymorphism (1,2), phase transitions (3,4), and hydrate forms (5,6). One of the major challenges has been assigning features observed in spectra obtained in the terahertz region; assigning of vibrational absorption bands has been difficult due to the complex intermolecular interactions in organic crystalline materials. But a number of groups have begun to attempt to interpret the spectral features observed in the terahertz region (7,8). The ability to generate terahertz radiation from a point source coupled with the fact that many pharmaceutical excipients are semitransparent in this region makes has resulted in the development of imaging systems capable of nondestructive, three-dimensional investigations of solid dosage forms. Terahertz radiation generated at a source can penetrate up to several millimeters into a sample, and whenever there is change in refractive index due to either a change in chemistry or physical (that is, layers) characteristics of the tablet, a reflection results. This reflection is a ballistic reflection that occurs from the surface of the interfaces within a pharmaceutical product and because of the finite speed of light, occurs at different times. We are able to make use of the time-of-flight capabilities of the technique to discriminate between pulses coming from different boundaries in the sample and randomly scattered photons (9,10). By measuring the differences between pulses arriving at different times, maps of the coating thicknesses of dosage form can be obtained. This can be done not only for the top surface but multiple surfaces within the products. Ho and colleagues (11) used the technique to investigate the scale-up failure between a laboratory (4-kg) scale batch and a pilot (20-kg) batch. The researchers reported significant differences in the dissolution profiles of the two batches, which they assigned to differences in the density of coatings. They also were able to develop a robust partial least squares (PLS) model to predict mean dissolution time from the raw terahertz waveform. More recently, Malaterre and colleagues (12) reported the correlation between the coating thickness on push–pull osmotic pump tablet; the thicknesses were obtained via terahertz pulsed imaging and the mean dissolution time. The authors also report the observation of internal within the coating, which correlated to an interruption to the coating process.

Figure 1

Until now, much of this work has been achieved with laboratory-based instruments measuring tablets at high spatial resolution. In this column, we review the progress from the laboratory into the process environment and the monitoring of coating applied to solid dosage forms in-line.