Since initial research on terahertz radiation began to gain momentum nearly 20 years ago, this technology has evolved from being a pure research tool to one that is used for pharmaceutical applications. More specifically, techniques using pulsed terahertz radiation such as terahertz pulsed spectroscopy (TPS) and terahertz pulsed imaging (TPI) are now increasingly employed to analyse solid dosage forms. So far, TPS has been predominantly used to acquire physical information of solid-state properties of active pharmaceutical ingredients (APIs), particularly in the field of polymorph recognition, characterization and quantification.

TPI can be used to nondestructively analyse tablet matrix physicochemical composition, coatings and buried interface properties in solid oral dosage forms because of its pulsed and coherent nature of the radiation together with its frequency-dependent unique penetration characteristics. In addition, both two- and three-dimensional (2D, 3D) imaging techniques are currently being developed.^1–3

Terahertz radiation

Terahertz technology

Figure 1 Setup of the TPS system (left) and the TPI system (right).

In contrast to conventional far-infrared spectroscopy, terahertz radiation is unique in that its generation by the photoconductive antenna is coherent and pulsed.⁵ Moreover, compared with most other spectroscopic techniques, in TPS and TPI the photo-induced electrical field is measured directly rather than just its signal intensity. Using the information on the amplitude and phase of the signal both the absorption coefficient and the refractive index of the sample can be measured directly.^1,5

After performing a Fourier transformation of both sample and reference waveform into the frequency domain, the terahertz absorbance spectrum is calculated. For the structural image generation in TPI, the measured time delay originating from reflections at interfaces within the sample in the time domain waveform is used to resolve the depth dimension. Spatial information (horizontal and vertical dimensions) is obtained by fully automated point mapping of the sample. This TPI waveform data for each pixel can also be Fourier transformed to yield a fourth dimension with spectral information of the sample. Using this approach, both structural information and chemical composition in the sample can be described using TPI.^5–7

TPS and polymorph recognition

Polymorphism is a solid-state phenomenon where, though possessing the same chemical structure, pharmaceutical solids may exhibit different arrangements of their molecules in the unit cell, leading to subsequent physicochemical differences for these modifications for properties such as bioavailability, processibility and stability. The prevalence of polymorphism in pharmaceutical solids and the paramount importance in its identification are consistently highlighted in the literature.^6–9 TPS has been used to distinguish amorphous, crystalline, hydrate, solvate and liquid crystalline solid states in a number of drug molecules. It is now commonly accepted in the literature that terahertz spectra provide sufficient information to distinguish subtle differences in condensed matter properties.