Rising Interest in Terahertz Spectroscopy in Pharmaceutical Analysis

Spectroscopy—the analysis of the properties of substances based on their interactions (absorption, transmission, reflectance) with electromagnetic radiation—is a fundamental analytical tool in the pharmaceutical industry. Commonplace methods, including infrared (IR) and ultraviolet-visible (UV-vis), and newer methods, such as near-infrared (NIR) and Raman, spectroscopy, use radiation of different wavelengths (i.e., energies) to provide unique information about the structure and electronic configuration of different compounds. Terahertz spectroscopy is the newest entrant on the block, and this low-energy technique is attracting a lot of attention due to its ease-of-use, rapid analysis time, depth of penetration into solid materials, and its ability to provide a wide range of physical and material property information.

Terahertz waves fall on the electromagnetic spectrum between the infrared and millimeter wave regions (300 gigahertz to 10 terahertz, see Figure 1). They are transmitted through many types of materials, such as tablets, capsules, gels, and even liquids and slurries, which enables the analysis of their internal structure. Notably, the intermolecular vibrations between small molecules and the intramolecular vibrations of larger molecules (peptides and proteins) as they fold around themselves occur at this wavelength. Terahertz spectroscopy can thus be used to determine the chemical composition of substances, the presence of impurities, and other properties. In addition, by comparison with a known spectrum, differences between pharmaceutical products such as tablets can be analyzed nondestructively.

Recently, the cost and size of terahertz instrumentation has decreased significantly to the point where it is now a practical tool for industrial applications, including for pharmaceutical development and manufacturing, according to Ed King, an R&D fellow at Advantest Corporation. He also points to the increasing number of presentations given at conferences and papers appearing in the published literature as evidence that the utility of terahertz spectroscopy is being recognized in the academic community.

Generating a terahertz wave
Like many other spectroscopes, terahertz instruments generally have an emitter and a detector (see Figure 2). In this case, femtosecond laser pulses are shined on the detector, causing the emission of energy in the terahertz region. These sub-picosecond pulse duration emissions are directed at the sample and are transmitted, reflected or absorbed. A second laser is then used to digitally sample the waves that are generated after interaction with the substance being analyzed. A single scan can be processed in various ways (e.g., Fourier transforms, time-of-flight analysisto generate a useful spectrum in as little as 8 milliseconds.

“The spectrum of a sample is a unique fingerprint of the interactions (hydrogen bonding, dipole-dipole, and Van der Waals) between small molecules and within larger molecules, providing, for example, crystal lattice information,” observes David Heaps, a principal scientist with Advantest.

Most importantly, rapid, nondestructive imaging and analysis of pharmaceutical samples in the liquid or solid state is possible. “Crystalline qualities, the characteristics of constituents, and even the thickness, density, and internal structure of tablet coatings—previously impossible to analyze nondestructively—may be evaluated and visually rendered in two or three dimensions,” adds King.

The Advantest system uses a proprietary, in-house-developed broadband emitter using an optical rectification-type, terahertz-wave generation scheme to generate spectral coverage from 0.5 to 7 THz. In addition, spectrometry tailored to various dosage forms—from liquids to solids—and the analysis of physicochemical properties are made possible by simply exchanging the measurement module from transmission to reflectance or to attenuated total reflection, according to senior R&D scientist Mark Sullivan at Advantest (see Figure 3).

Numerous applications
Tablet coatings can be highly complex systems that consist of multiple layers, contain APIs, and serve a functional purpose (i.e., sustained-release, taste masking) beyond providing the appearance of the dosage form. As the complexity of such coatings increases, the uniformity of the thickness and distribution of active ingredients, interactions between multiple layers and the tablet core, and coating stability all become critical quality parameters, according to King.

 By analyzing the time-delay and amplitude of terahertz wave pulses reflected by different coating layers with different refractive indices, the thickness and density of the layers can be evaluated as can the interfacial adhesion between the layers and the tablet. Changes in the results obtained over a period of time can indicate migration of ingredients within the coating or from the coating to the tablet.

Furthermore, because terahertz waves can penetrate up to a few millimeters into a solid, the chemical composition of the tablet itself can be evaluated(see Figure 4). In addition to the distribution of ingredients in a tablet, the density and porosity can be determined. This analysis gives results similar to those that are obtained using the hardness test, which requires destruction of the tablet. Terahertz spectroscopy has also been proposed for the evaluation of the uniformity of the density of ribbons produced by roller compaction.

Analysis of polymorphs is also possible. Terahertz spectroscopy gives results similar to those obtained using X-ray powder diffraction, but there are no safety issues associated with low-energy terahertz radiation, and the results are obtained much more rapidly, according to Sullivan.

Absorption in the THz frequency range is sensitive to crystal-lattice vibrations. These absorptions result in a characteristic spectrum for each crystal form, thus enabling the analysis of polymorphs. “Rapid evaluation is becoming increasingly important as poorly soluble drugs begin to be formulated as cocrystals. In solid-form discovery, maybe 10 different pure polymorphs, hydrates, or salts will be screened to select the best candidates for development. The number of possible forms for cocrystals is significantly higher, perhaps even comprising a combinatorial library of possible forms,” he notes.

Terahertz spectroscopy is also useful for the evaluation of the physical stability of amorphous dispersions of poorly soluble drugs. In all of these cases, being able to extensively characterize the solid form of APIs is critical for establishing a strong intellectual property position.

PAT potential
The ability to rapidly acquire spectra makes terahertz spectroscopy suited for use in process analytical technology (PAT) applications, according to Heaps. “In many of the aspects of pharmaceutical manufacturing where continuous processing is being actively explored, there is a great need for vary rapid analytical techniques that can be used to provide real-time information.  Terahertz spectroscopy is very attractive for this application because it can be used to monitor multiple different properties very rapidly, and can be used equally effectively for R&D, pilot plants, and commercial-scale production,” he adds.

Many advantages
A key advantage of terahertz spectroscopy is that it enables the analysis of many material properties that traditionally have required the destruction of the sample. The greater penetration of terahertz waves probes sample depths that are not obtainable using most spectroscopic techniques, and its high sensitivity allows for limits of detection of < 1% for minor components in a sample. In addition, it does not present any safety hazards, unlike X-ray analysis, and extensive operator training is not required with the instrumentation available today. Finally, terahertz spectroscopy can be used to complement FTIR, NIR, Raman, and X-ray powder diffraction, and its speed of measurement makes it attractive for online measurement.