Terahertz Radiation
Terahertz radiation has excellent potential to help with the understanding of fundamental and exciting new challenges at the interface between physics, materials chemistry and the life sciences but it is, as yet, largely unexplored. Light located in this range of the electromagnetic spectrum was very difficult to generate until quite recently. Since the 1990s new developments in semiconductor physics and femtosecond laser technology have made it possible to provide light at terahertz frequencies (a frequency of 1 THz equals a wavelength of 0.3 mm) in a relatively simple way.
Terahertz radiation has unique properties in that it easily penetrates through most polymeric materials and is therefore an exciting new tool to study such materials, which are often opaque at visible frequencies. As well as being a non-destructive probe of materials, in organic molecular crystals terahertz radiation has the important property that it interacts with vibrational modes that extend across large domains of a crystal lattice. This makes terahertz spectroscopy unique: even though it is possible to excite molecules using a variety of energies it is only through the careful selection of the low energy in the terahertz range that it is possible to selectively excite crystal lattice vibrations and study in a unique way the presence and nature of interactions between molecules.
By using terahertz spectroscopy our group is aiming to understand the physical characteristics of a wide variety of materials spanning the fields of pharmaceuticals, catalysis, biologicals, nanotechnology and non-destructive testing.
Over the past five years, our group has achieved substantial progress in refining THz measurement techniques and applying them to unravel complex processes. Our research sheds light on critical questions, from the detailed mechanics of how medicines dissolve and release their active ingredients within the body to the fundamental behaviour of materials at the molecular level. Our success stems from skillfully matching the distinctive physics of THz radiation – its ability to pass through packaging and coatings, its sensitivity to water, and its capacity to distinguish different physical forms like crystal structures – to specific analytical needs where conventional methods may be insufficient or destructive. This strategic application positions us not only as experts in THz physics but as innovators creating practical THz solutions for pressing scientific and industrial problems. This summary highlights the key breakthroughs and thematic advancements emerging from our recent publications.
Advancing Pharmaceutical Quality and Understanding
A major focus of our research lies in the pharmaceutical domain, where ensuring the quality, safety, and efficacy of medicines is paramount. We use terahertz technology to offer non-destructive ways to probe the critical properties of drugs and their delivery systems, leading to better products and more efficient manufacturing.
Peeking Inside Pills: Ensuring Medication Works as Expected
For a tablet medication to be effective, it must break apart (disintegrate) and release its active pharmaceutical ingredient (API) to be absorbed by the body (dissolution) in a predictable manner. Understanding precisely how this happens inside the tablet is crucial for designing effective formulations. We employ Terahertz Pulsed Imaging (TPI) and Terahertz Time-Domain Spectroscopy (THz-TDS) as powerful tools to visualise and quantify these processes in real-time, without cutting open or destroying the tablet. Using these techniques, we track liquid ingress into the tablet's porous structure, observe how protective or functional coatings influence this water uptake, and monitor the changes in its internal architecture as it swells and breaks down. This provides invaluable insights into how different formulation components, such as disintegrants (which promote breakup) and lubricants (which aid manufacturing), along with the manufacturing process itself, ultimately dictate the medicine's performance.
Our recent work vividly illustrates these capabilities. We have used TPI to directly visualise the pathways of liquid transport through coated tablets, revealing how the coating affects the initial stages of disintegration (Dong & Zeitler, 2022). Subsequent studies investigated the specific impact of immediate-release film coatings on the overall disintegration process and the subsequent dissolution of the drug (Ma et al., 2024; Dong et al., 2023). We meticulously analysed the influence of key excipients, like croscarmellose sodium (a common disintegrant) and magnesium stearate (a lubricant), on tablet hydration and disintegration using THz methods (Lee et al., 2025). Going beyond simple disintegration, we have even developed calorimetric methods, potentially combined with THz analysis, to investigate the heat released during tablet disintegration (Lee et al., 2024), adding another layer of understanding to the process. The versatility of THz extends to more complex drug delivery systems as well; we have conducted studies examining drug release mechanisms from specialised implants designed for targeted delivery (e.g., to the inner ear,(Bedulho das Lages et al. 2024)) and from drug-loaded microparticles embedded within hydrogels (Lefol et al., 2024).
Smarter Manufacturing: Real-Time Quality Control
Traditional pharmaceutical manufacturing often relies on testing batches of finished products to ensure quality. However, a modern approach, known as Process Analytical Technology (PAT), aims to build quality into the product by monitoring the manufacturing process continuously in real-time. This allows for immediate adjustments and ensures consistency throughout production. THz-TDS is emerging as a highly promising PAT tool, capable of measuring critical quality attributes non-destructively and rapidly. Our group has been instrumental in demonstrating the potential of THz-TDS for monitoring key parameters like tablet porosity – the amount of empty space within the tablet, which significantly impacts disintegration and dissolution – and the internal structure resulting from processes like powder compaction and granulation. Measuring these properties quickly and without damaging the product is a major challenge using traditional techniques, highlighting the unique advantage of THz sensing.
Our specific achievements in this area over the last five years include developing and refining THz-TDS methods to accurately quantify tablet porosity ((Bawuah et al. 2020);(Bawuah et al. 2023)), even providing information about the shape and orientation of the pores using anisotropic models and performing detailed error analyses (Anuschek et al., 2021). Building on this, we demonstrated techniques using THz reflection measurements for the simultaneous determination of both tablet porosity and height (Anuschek et al., 2023), offering more comprehensive quality assessment. We extended the application of THz-TDS to monitor the blending process, ensuring that the active drug and other ingredients are uniformly mixed before tablet compression – a critical step for dose consistency (Anuschek et al., 2024). Our proof-of-concept studies have shown THz can monitor blend homogeneity and even assess tablet mass during production (Anuschek et al., 2024). Furthermore, we used THz scattering analysis to quantify the degree of particle fragmentation occurring during the tablet compression process ((Skelbæk-Pedersen et al. 2020)), providing insights into the mechanical properties of the formulation. This body of work supports the vision of "real-time release testing," where continuous THz monitoring during manufacturing could potentially allow batches to be approved immediately upon completion (Markl et al., 2020), significantly speeding up production and release processes. Our focus on THz as a PAT tool signifies a move towards more efficient, reliable, and preventative quality control strategies in pharmaceutical manufacturing, shifting away from a sole reliance on end-product testing and potentially reducing costs, improving consistency, and enhancing patient safety.
Decoding Drug Ingredients: Stability and Performance
The physical form of the active pharmaceutical ingredient within a tablet is critically important. Drugs can exist in different crystal structures (polymorphs) or in a non-crystalline (amorphous) state. These different forms can have vastly different properties, including stability (how long the drug remains effective), solubility (how well it dissolves), and ultimately, bioavailability (how much drug reaches the bloodstream). THz spectroscopy is exceptionally sensitive to the subtle differences in molecular arrangement and collective vibrations that distinguish these solid-state forms. We leverage THz-TDS to characterise these forms accurately, a crucial step in drug development and quality control. A particular challenge is ensuring that amorphous drugs, often used to improve solubility, do not crystallise over time, as this can drastically reduce their effectiveness. THz spectroscopy provides a non-invasive way for us to detect even small amounts of unwanted crystallinity within amorphous formulations.
Examples from our recent work include using THz spectroscopy to detect and quantify crystallinity in amorphous solid dispersions created using advanced manufacturing techniques like 3D printing ((Santitewagun et al 2022)). Our low-frequency vibrational analysis using THz has provided new structural insights into the well-known, yet complex, polymorphic forms of aspirin (Li et al., 2022). We applied similar techniques to understand the metastability (tendency to change form) of different crystalline forms of theophylline, another common drug (Paiva et al., 2021). We have also investigated processes designed to create amorphous drugs, such as microwave-induced amorphisation (Hempel et al., 2020; Hempel et al., 2021) and formulation strategies for heat-sensitive drugs (Davis Jr. et al., 2021), using THz to assess the outcomes. More recently, we employed THz imaging to track the transformation of inactive ingredients (excipients) within a tablet coating from their anhydrous (water-free) state to a hydrate (water-containing) state during exposure to moisture (Ma et al., 2025), demonstrating the ability of THz to monitor subtle, water-mediated structural changes in complex formulations.
Our research across these pharmaceutical areas demonstrates a powerful, multi-scale approach. By using THz techniques, we connect the macroscopic performance of a tablet – how it breaks apart and releases its drug – to its microscopic properties, such as the internal pore network, the structure of its coating, the physical form of the drug, and the fragmentation of its constituent particles. This ability to link different scales provides a holistic, physics-based understanding of tablet behaviour. Such detailed understanding, which we achieve through non-destructive THz analysis, facilitates more rational design of drug formulations and the development of more robust and reliable manufacturing processes, ultimately contributing to better and safer medicines.
Table 1: Pharmaceutical Applications of Terahertz Technology Explored by Our Group (2020-2025)
Exploring the Nanoscale World: From Proteins to Polymers
Beyond the direct applications in pharmaceuticals, we also utilise THz spectroscopy to probe the fundamental behaviour of matter at the molecular and nanoscale level. This foundational research not only advances basic science but also provides a deeper understanding that strengthens our applied work.
Understanding Molecular Interactions
The energy of terahertz radiation corresponds directly to the energy scales of important collective motions within materials. These include the vibrations of entire molecules within a crystal lattice, the twisting and flexing modes of large molecules, and the vibrations of the hydrogen bond networks that structure liquids like water. This makes THz spectroscopy an exquisitely sensitive probe for studying these fundamental dynamics. We apply THz techniques to investigate these subtle molecular motions in a wide range of systems, from simple liquids and glasses to complex and biologically crucial molecules like proteins. Understanding these dynamics is key to predicting macroscopic material properties (like stability, flexibility, and phase transitions) and biological function.
Our recent fundamental studies include exploring the complex molecular dynamics in mixtures, such as the glycerol-water system, across different temperatures and concentrations (Kölbel et al., 2023). We have investigated the so-called "dynamical transition" in dehydrated proteins using THz spectroscopy (Kölbel et al., 2024); this transition is thought to be related to the onset of functional motions and is critical for understanding protein stability, particularly in dry formulations relevant to biopharmaceuticals. In collaboration, we have explored the link between the mobility of water molecules surrounding proteins and the tendency for these proteins to aggregate – a process implicated in neurodegenerative diseases like Alzheimer's ((Stephens et al. 2022)). This work suggests that decreased water mobility, potentially measurable by THz techniques, can enhance harmful protein aggregation. Other studies have focused on observing the collective molecular motions that occur as crystals form from solution (Li et al., 2022), providing insights into the crystallisation process itself, and probing the detailed nature of lattice dynamics (vibrations of the crystal structure) in molecular crystals by combining THz spectroscopy with X-ray diffraction (Hutereau et al., 2020). Our fundamental work even extends to questioning established classifications of materials based on their THz response, as seen in studies of glass-forming liquids like ortho-terphenyl (Kölbel et al., 2024).
Characterising Advanced Materials
Our expertise in THz analysis also extends to characterising processes and properties in other advanced materials beyond the biological and pharmaceutical realms. This includes investigating how liquids permeate and interact with porous materials, which is crucial for applications such as industrial catalysts, filtration systems, separation processes, and even construction materials. Furthermore, we apply THz techniques to characterise polymers, ubiquitous materials found in everything from packaging to high-performance composites.
Specific examples include our use of THz pulsed imaging to study the kinetics of liquid transport within porous compacts made from α-alumina powder, a common ceramic material. These studies examined how factors like the degree of sintering (heating to bond particles) and the type of solvent used affect the rate and mechanism of liquid penetration ((Al-Sharabi et al. 2021a);(Al-Sharabi et al. 2021b)). In another application, we used THz-TDS to non-destructively sense the absorption of water in epoxy materials that had undergone hygrothermal ageing (exposure to heat and humidity) (Lin et al., 2021). Understanding water uptake is critical for predicting the degradation, durability, and long-term performance of polymer-based materials and adhesives.
This fundamental research into molecular dynamics and material characterisation provides a crucial scientific foundation for our applied pharmaceutical work. For instance, understanding precisely how THz radiation interacts with water molecules and hydrogen bond networks is essential for accurately interpreting the THz signals we measure during tablet hydration and disintegration studies. Similarly, fundamental knowledge of how THz spectra relate to crystal lattice structures and amorphous states enhances our ability to characterise drug polymorphs and detect unwanted crystallinity in pharmaceutical formulations. This synergy creates a powerful feedback loop: applied challenges in complex systems like tablets can inspire fundamental questions about THz-matter interactions, while deeper fundamental understanding enables us to develop more sophisticated and reliable applied THz measurement techniques.
Pushing the Frontiers of Terahertz Science
In addition to applying THz technology to solve specific problems, we are actively involved in advancing the technology itself. This involves developing novel experimental setups, creating more sophisticated data analysis methods, and contributing to efforts that make THz science more robust and accessible to the wider scientific community. These methodological improvements enhance the capabilities and reliability of THz measurements across all fields of application.
Our significant contributions in this area over the past five years include the design and implementation of an enhanced experimental setup specifically tailored for in-situ investigation of liquid transport during pharmaceutical tablet disintegration (Lee et al., 2023), allowing for more detailed analysis. We developed a specialised flow cell to enable in-situ THz-TDS studies of crystallisation processes as they happen (Li et al., 2022). We have also established robust methods for accurately measuring solute concentration in solutions, even within multiphase systems like suspensions, using THz-TDS (Kölbel et al., 2022). We advanced data analysis through the application of optimised waveform selection and recurrent neural networks for processing THz signals, particularly in the context of monitoring pharmaceutical coating processes (Li et al., 2022). Furthermore, we performed rigorous error analysis for specific THz data interpretation models, such as the anisotropic Bruggeman model used for porosity measurements (Anuschek et al., 2021), leading to more reliable results.
Perhaps one of our most impactful contributions to the broader field has been the initiation and leadership of the "dotTHz project." This initiative resulted in the development and publication of a standardised data format specifically for terahertz time-domain spectroscopy data (Lee et al., 2023). Establishing such a standard is crucial for facilitating data sharing, comparison of results between different laboratories, and collaborative research efforts. It represents a significant step towards maturing THz-TDS from a collection of specialised laboratory techniques into a more unified and widely applicable analytical tool. This focus on standardisation, alongside our publication of educational tutorials ((Bawuah et al. 2020)) and comprehensive reviews on THz applications and techniques ((Bawuah and Zeitler 2021); Alves-Lima et al., 2020), demonstrates our commitment to building the infrastructure of the THz field. Our active participation in shaping the international 2023 Terahertz Science and Technology Roadmap (Leitenstorfer et al., 2023) further underscores our leading role and engagement with the global research community's goals. These efforts collectively lower the barrier to entry for new researchers and industrial users, fostering wider adoption and potentially accelerating innovation across diverse scientific and technological domains.
Looking Ahead: The Future of Terahertz Applications
The research we have conducted over the last five years has demonstrably advanced our ability to analyse and understand complex materials and processes, particularly within the pharmaceutical industry. By harnessing the unique properties of terahertz radiation, we have pioneered non-destructive methods for 'seeing inside' tablets to observe disintegration and drug release, developed powerful tools for real-time quality control in manufacturing, and provided new ways to characterise the critical solid-state structures of drug ingredients. Our work also extends to fundamental studies of molecular dynamics in liquids, proteins, and crystals, as well as the characterisation of advanced materials like ceramics and polymers.
The future of terahertz science and technology looks exceptionally bright, driven by the foundational understanding and methodological improvements we and other leading groups pursue. Continued advancements promise even more sophisticated applications. We anticipate the development of faster, more integrated THz systems, potentially enhanced by artificial intelligence for automated data analysis and process control, as hinted by our work on optimising THz waveform analysis (Li et al., 2022). These innovations can further revolutionise pharmaceutical development and manufacturing, leading to safer, more effective, and more consistently produced medicines. Beyond pharmaceuticals, the ability to probe molecular interactions and material structures non-invasively with terahertz radiation will undoubtedly unlock new scientific discoveries and technological capabilities across chemistry, materials science, and biology, truly allowing us to 'see' the world through the revealing terahertz window.