Tablet coatings are of great importance to both consumers and pharmaceutical manufacturers. By controlling the release of the active pharmaceutical ingredient, tablet coatings ensure bioavailability and minimize harmful effects and the waste of the drug by delivering it at the specific site and at the optimum level. These functions can be compromised if a coating is nonuniform or has defects.

The exceptional properties of terahertz radiation — including its low photon nonionizing energies and its ability to penetrate most nonpolar materials that can be opaque for visible light or low contrast for X-rays — make this radiation a very attractive tool for helping to understand pharmaceutical materials and products.

Until recently, the analysis of coating thickness relied upon indirect techniques, and it usually was determined by the weight gain of the coated tablet compared to the uncoated tablet core. Near-infrared (NIR) and Raman spectroscopic and imaging techniques that have been developed in recent years to yield information about the quality and integrity of the coatings usually are restricted to the outer surface of the tablet. To test the coating for uniformity or to analyze buried structures or even multiple layers within the tablet, the tablet must be cut and spectroscopic images must be acquired for each layer. However, in contrast to the NIR and mid-IR regions of the electromagnetic spectrum, many of the excipients used for coating solid dosage forms are transparent or semitransparent to terahertz radiation. Moreover, terahertz radiation can easily penetrate commonly used coating polymers. This in turn means that, unlike the aforementioned techniques, terahertz pulsed imaging (TPI) nondestructively provides spatially resolved information from below the surface of the sample (tablet). A nondestructive alternative for characterizing only the density variations within the tablet, and therefore only physical properties of a sample, is X-ray microtomography. However, long acquisition times, computational requirements, and the possibility of radiation-induced strain in the sample are limitations of this technique. Consequently, terahertz measurements are arguably more suited than any of the aforementioned techniques to monitor key quality attributes of the pharmaceutical solid dosage forms during manufacturing.

The 3D TPI measurements discussed in this column were performed using a TPI imaga 2000 system (TeraView, Cambridge, UK).

The method employed to generate terahertz pulsed radiation is based upon illuminating a biased photoconductive switch (antenna) by a femtosecond laser pulse with a photon energy greater than the bandgap of a gallium arsenide substrate. This process will lead to production of photocarriers — electrons and holes in the conduction and valence bands, respectively. Fast varying density of the photocarriers and their acceleration in the external field of the applied bias will generate an electromagnetic field radiating into free space in the terahertz frequency range. The nature of terahertz pulse is broadband (typically 0.06–3 THz, corresponding to 2–100 cm^-1 ).

The detection of the incident terahertz pulse is also based upon a photoconductive antenna. Assuming that an above-band gap optical gating pulse is focused onto a photoconductive antenna-based detector, it will produce photocarriers in the antenna substrate. An incoming terahertz beam will induce a transient bias voltage across the antenna gap between the electrodes. If the incident terahertz electric field and induced photocarriers are both present, the photocurrent will flow across the gap. This current is proportional to the terahertz electric field. By varying the optical path length between terahertz and optical pulses, the entire terahertz time-domain signal can be sampled with both the amplitude and phase of the terahertz pulse available. This is in contrast to most spectroscopic techniques that yield only the signal intensity.

Figure 1

The components of the TPI system are shown in Figure 1. A Ti:sapphire laser provides a train of laser pulses that are split into a pump beam for terahertz generation and a probe beam for detection, both based upon photo-excitation of a gallium arsenide antenna. These two optical pulses are launched into separate optical fibers that link the TPI core unit with the tablet scanning unit. After leaving the output from the optical fibers in the tablet scanning unit, the pump and probe beams are focused onto the gaps of the photoconductive emitter and detector, respectively, using a silicon lens. A modulated bias was applied across the emitter electrodes and the detector gated output signal was fed to a lock-in amplifier. Reference for the lock-in is provided by the electric modulation of the emitter. A dynamic range of greater than 70 dB was demonstrated using time-gated and lock-in detection. To record the time evolution of the terahertz electric field, a rapid scan delay line is incorporated in the probe beam that systematically varies the delay between probe and pump beam at the detector. The generated terahertz signal from the emitter is focused by a silicon lens to a diffraction-limited spot on the tablet surface. The terahertz radiation reflected from the tablet is collected by the same silicon lens and focused onto the detector.

Prior knowledge of the tablet shape profile allows a six-axis robot arm to position the solid dosage form under investigation in focus and always normal to the incident terahertz beam. In this manner, a 3D terahertz image of the solid dosage form is acquired. When the terahertz pulse is applied on a tablet, part of the incident terahertz pulse is reflected from the tablet's outer surface. The other portion passes into the tablet and is partially reflected every time it encounters a new subsurface within the tablet, characterized by a different index of refraction. The resulting terahertz waveform thus consists of multiple pulses arriving at the detector at delayed times, depending upon the index of refraction and the thickness of the traversed layer.