Johannes Kiefer- University of Bremen, Engineering Thermodynamics and MAPEX Center for Materials and Processes
Abstract
Terahertz spectroscopy utilizes a spectral range that is characteristic of low-frequency vibrational modes, molecular rotational modes as well as intermolecular interactions. Hence, it is capable of molecular fingerprinting and a suitable means of pharmaceutical analysis. This article aims at giving a brief introduction to THz spectroscopy and its applications to pharmaceutical products.
The THz
Region The spectral range of terahertz (THz) spectroscopy represents the regime between microwave and infrared spectroscopy, see Figure 1. Microwave (MW) spectroscopy is known as a means of pure rotational spectroscopy utilizing frequencies below 0.1 THz, while infrared (IR) spectroscopy is a classical form of vibrational spectroscopy taking advantage of the range above 10 THz. Owing to difficulties in building high-performance radiation sources and detectors in the 0.1-10 THz range at reasonable costs, THz spectroscopy has begun its success story as a valuable analytical tool only about two decades ago. It is capable of accessing low-frequency vibrational modes, molecular rotational modes as well as intermolecular interactions. For a general overview of THz spectroscopy and technology see References 1 - 3.
Like other optical methods such as Raman or infrared spectroscopy, THz spectroscopy allows for non-contact measurements. Moreover, many materials transmit THz radiation so that targets inside their containers may be analyzed. The low photon energy of THz radiation is an advantage and a disadvantage at the same time: an advantage because low energy means a low impact on the sample so that, for instance, photo-dissociation will not take place; a disadvantage because a low impact may result in no detectable response. Nevertheless, most organic materials deliver a characteristic THz spectrum so that the method can be characterized as a versatile tool for pharmaceutical analysis.
THz spectroscopy can be applied in many ways including:
- classical frequency-domain spectroscopy for qualitative and quantitative chemical analysis
- temporally resolved spectroscopy
- time-resolved spectroscopy
- imaging with chemical contrast
- tomographic imaging
All of these can be used in the pharmaceutical sector. These different modes of operation are illustrated in Figure 2.
Methods and Applications
The classical frequency-domain approaches (Figures 2a and 2b) can be realized in multiple ways like those in conventional IR spectroscopy: e.g., in transmission, in attenuated total reflection (ATR), and in reflection. The resulting spectra look similar to IR or Raman spectra presenting peaks and signatures that are characteristic of the molecules in the sample. They enable the identification and quantification of the individual species. Hence, they can be employed to determine the chemical composition of a tablet, the molecular concentration of pharmaceutically active ingredients, of excipients, and of contaminants can be measured. When the instrument is capable of recording spectra at a reasonable repetition rate and acquisition time, the temporal evolution of the THz spectrum can be monitored, e.g. to follow chemical conversion processes during the formulation of a product. The analysis of drug polymorphs to develop an understanding of polymorphic inter-conversion dynamics is one example for such an application. For instance, Zeitler et al.4 investigated the enantiotropic solid-state phase transition between the two polymorphs of carbamazepine. This process took place over a period of several hours so that recording a spectrum every 60 minutes was sufficient. Typical instruments, however, can easily reach acquisition times of seconds and hence allow for a rapid measurement.
Time-resolved spectroscopy is a fundamentally different technique: ultrashort pulses of THz radiation are used to initially excite the species of interest and then the molecular state is probed by a time-delayed pulse (pump-probe technique). When the pulses are sufficiently short, the ultrafast dynamics of molecular motions and chemical reactions can be analyzed. The review article by Smith and Arnold5 gives a good overview of time-domain experimentation and also covers the early years of pharmaceutical applications.
Planar imaging and tomographic imaging techniques have become very popular as they allow chemical maps in 2D and 3D to be obtained. For instance, they can be used for determining the integrity and homogeneity of product cores and coatings, see for example Reference 6. The emerging application of chemometrics and deep learning methods to analyze the data is a particularly interesting point in this context. This will allow the evaluation of large data sets, especially when hyper-spectral data are available, i.e. each pixel in an image or voxel in a tomographic image is backed with a full spectrum containing all the detailed information. So multidimensional chemical maps can be derived that may help to identify potential issues in a product and to optimize the production process.
Conclusion
In this article, THz spectroscopy for the analysis of pharmaceuticals has been introduced. Its different modes of operation complement the pharmaceutical analytics toolbox with methods for qualitative and quantitative analysis, imaging and tomography capabilities, and potential inline sensing applications. The list of key features includes that (1) the THz spectrum represents a molecular fingerprint of the sample, (2) the spectrum is obtained in a non-contact and non-destructive measurement, (3) high measurement repetition rates are possible, and (4) virtually all relevant materials are at least semi-transparent at THz frequencies so that both surface and core of e.g. a tablet can be assessed. Disadvantages include the relatively high costs and maintenance effort, especially when ultrashort-pulse lasers and cryogenically cooled detectors are involved. The development of these devices is progressing rapidly and hence THz spectroscopy – even time-domain THz spectroscopy – becomes more and more user friendly; a number of straightforward and easy-to-use THz instruments are already on the market.
References
- S.S. Prabhu, Chapter 4 - Terahertz Spectroscopy: Advances and Applications, in V.P. Gupta (editor), Molecular and Laser Spectroscopy, Elsevier, 2018.
- K.-E. Peiponen, J.A. Zeitler, Terahertz spectroscopy theory, in J.C. Lindon, G.E. Tranter, D.W. Koppenaal (eds.), Encyclopedia of Spectroscopy and Spectrometry (Third Edition), Academic Press, 2017.
- D. Saeedkia (ed.), Handbook of Terahertz Technology for Imaging, Sensing and Communications, 2013, Woodhead Publishing.
- J.A. Zeitler, P.F. Taday, K.C. Gordon, M. Pepper, T. Rades, Solid-State Transition Mechanism in Carbamazepine Polymorphs by Time-Resolved Terahertz Spectroscopy, ChemPhysChem 2007, 8, 1924-1927.
- R.M. Smith, M.A. Arnold, Terahertz Time-Domain Spectroscopy of Solid Samples: Principles, Applications, and Challenges, Applied Spectroscopy Reviews 2011, 46, 636-679.
- J.A. Zeitler, P.F. Taday, D.A. Newnham, M. Pepper, K.C. Gordon, T. Rades, Terahertz pulsed spectroscopy and imaging in the pharmaceutical setting - a review, Journal of Pharmacy and Pharmacology 2007, 59, 209-223.
About the Author
Johannes Kiefer is professor of engineering thermodynamics at the University of Bremen, Germany. His research interests include the development of optical spectroscopic methods for engineering and life science applications.
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