Measurement Principle
The measurement principle of TPI is very simple [1]: a pulse of THz radiation is focused on the surface of the coated tablet. Due to its ability to penetrate polymer materials a part of the THz pulse penetrates into the coated tablet while the remaining part of the pulse is reflected from the tablet surface due to the change in refractive index at the interface of air and coating surface. The part of the THz pulse that penetrated into the tablet undergoes subsequent reflections whenever others is a change in refractive index, such as at each interface between different coating layers. The measurement principle is similar to radar or ultrasound techniques.
The penetrative power together with the direct contrast mechanism due to the layer interface makes the TPI technique so powerful. There is no other technique on the market that can measure non-destructively at depth and resolve multiple layers at the same time without any need for chemometric calibration.
Off-line Analysis
By TPI it was possible to to reveal significant differences in coating thickness between the different surfaces of the same tablet as well as depending on the process conditions during which the tablets were coated [2]. With increasing process scale it was found that the release rate decreased for sustained-release coated tablets which was explained by the higher density of the coating layer, and thus lower diffusion coefficient, due to mechanical effects in the pilot scale coater compared to the lab scale coating process [3]. It was possible to directly correlate the TPI coating thickness measurements to the drug release rate from dissolution testing. This potentially means that for this type of coating it could be possible to predict the drug release profile of a coated tablet based on a TPI measurement of a coated tablet in applications such as real time release.
Using off-line measurements the TPI technology was used to investigate the coating process [4,5] and to carry out a detailed analysis into how coating weak spots affect the drug release [6].
http://www.pssrc.org/component/k2/26/microstructure-of-film-coated-tablets#sigProGalleria0c0d89c936
In-line Sensor Technology
Based on the potential of TPI for coating analysis a sensor was designed that was capable of in-line measurements of individual tablets within a perforated pan coater in real time under full production scale conditions [7]. The TPI approach is unique in that the sensor can directly measure the coating thickness distribution at any time point during the process. This is impossible with NIR or Raman process sensors as they are only capable of measuring a time or spatial average of the coating thickness based on chemometric models. In contrast, an individual TPI measurement takes less than 10 ms and no chemometric calibration is required.
TPI is a very powerful tool to develop advanced process understanding
Process Understanding
Using a design of experiments covering a wide range of coating process conditions we have recently demonstrated how TPI can be used to identify and optimise the critical process parameters for an active coating process to achieve optimal uniformity in terms of the intra-tablet coating thickness, and hence content uniformity. Such information would be very difficult, if not impossible, to obtain with any of the other established analytical technologies. The process understanding that was developed based on the terahertz analysis can be used to explain and validate the reading from PAT sensors such as Raman process control probes.
Validation
Extensive work was carried out to validate the TPI method [8,9] as well as to use TPI to guide the development of chemometric coating models for NIR and Raman process sensors [10] as well as together with optical coherence tomography [11].
Outlook
We have demonstrated the huge potential of TPI for pharmaceutical coating analysis. It is a very attractive technology for industrial applications as well as research and development: it is fast, non-destructive, requires little calibration and can provide information on multiple coatings on curved surfaces that cannot be measured with any other technique. We are confident that TPI will establish itself as the standard analysis tool for coated solid dosage forms.
References
[1] Zeitler, J., Shen, Y., Baker, C., Taday, P., Pepper, M., & Rades, T. (2007). Analysis of coating structures and interfaces in solid oral dosage forms by three dimensional terahertz pulsed imaging Journal of Pharmaceutical Sciences, 96 (2), 330-340 DOI: 10.1002/jps.20789 
[2] L. Ho, R. Mueller, M. Romer, K. C. Gordon, J. Heinamaki, P. Kleinebudde, M. Pepper, T. Rades, Y. C. Shen, C. J. Strachan, P. F. Taday, and J. A. Zeitler, J. Control. Release 119, 253 (2007), http://dx.doi.org/10.1016/j.jconrel.2007.03.011.
[3] L. Ho, R. Mueller, K. C. Gordon, P. Kleinebudde, M. Pepper, T. Rades, Y. Shen, P. F. Taday, and J. A. Zeitler, J. Control. Release 127, 79 (2008), http://dx.doi.org/10.1016/j.jconrel.2008.01.002.
[4] L. Ho, R. Mueller, K. C. Gordon, P. Kleinebudde, M. Pepper, T. Rades, Y. Shen, P. F. Taday, and J. A. Zeitler, J. Pharm Sci. 98, 4866 (2009), http://dx.doi.org/10.1002/jps.21766.
[5] L. Ho, R. Mueller, K. C. Gordon, P. Kleinebudde, M. Pepper, T. Rades, Y. Shen, P. F. Taday, and J. A. Zeitler, Eur. J. Pharm. Biopharm. 71, 117 (2009), http://dx.doi.org/10.1016/j.ejpb.2008.06.023.
[6] L. Ho, R. Mueller, C. Krueger, K. C. Gordon, P. Kleinebudde, M. Pepper, T. Rades, Y. Shen, P. F. Taday, and J. A. Zeitler, J. Pharm Sci. 99, 392 (2010), http://dx.doi.org/10.1002/jps.21845.
[7] R. K. May, M. J. Evans, S. Zhong, I. Warr, L. F. Gladden, Y. Shen, and J. A. Zeitler, J. Pharm Sci. 100, 1535 (2011), http://dx.doi.org/10.1002/jps.22359.
[8] Brock, D., Zeitler, J., Funke, A., Knop, K., & Kleinebudde, P. (2012). A comparison of quality control methods for active coating processes International Journal of Pharmaceutics, 439 (1-2), 289-295 DOI: 10.1016/j.ijpharm.2012.09.021
[9] I.-S. Russe, D. Brock, K. Knop, P. Kleinebudde, and J. A. Zeitler, Molecular Pharmaceutics 9, 3551 (2012), http://dx.doi.org/10.1021/mp300383y.
[10] J. Müller, D. Brock, K. Knop, J. A. Zeitler, and P. Kleinebudde, Eur. J. Pharm. Biopharm. 80, 690 (2012), http://dx.doi.org/10.1016/j.ejpb.2011.12.003.
[11] S. Zhong, Y.-C. Shen, L. Ho, R. K. May, J. A. Zeitler, M. Evans, P. F. Taday, M. Pepper, T. Rades, K. C. Gordon, R. Mueller, and P. Kleinebudde, Opt. Laser Eng. 49, 361 (2011), http://dx.doi.org/10.1109/ICIMW.2010.5612668.
PSSRC Facilities
The group of Dr Axel Zeitler at Cambridge has extensive experience with THz technology. The group has a number of custom made THz spectrometers as well as its own commercial TPI coating imaging system (Teraview TPI imaga 2000) and complementing technology to investigate dosage form microstructure, such as a Skyscan X-ray microtomography system.
In addition there is a wide range of expertise on film coating of tablets and pellets within the cluster in the centres in Düsseldorf, Copenhagen, Ghent and Lille.
http://www.pssrc.org/component/k2/26/microstructure-of-film-coated-tablets#sigProGalleriac33a47844e
Videos
Tablet imaging using a TPI imaga 2000 (TeraView Ltd. Cambridge, UK) fully automated tablet imaging system. The video is edited and shows the scan under accelerated playback. The total acquisition time for an entire tablet is about 30-60 min depending on sample size and resolution.
Video of the virtual THz cross-section through the coating structure of a sugar coated pharmaceutical tablet. In this representation the surface of the tablet is projected into a plane and all the coating structure is plotted relative to the surface. This representation is similar to the B-scan representation in ultrasound analysis. Note the detailed structure that can be resolved from within the sugar coating as well as the density inhomogeneities within the tablet matrix. The coating layer is clearly much thicker in the centre of the tablet compared to the edges.
3D reconstruction of a THz pulsed imaging dataset obtained from a tri-layered pharmaceutical tablet. The dataset was acquired in reflection. The green surface is the outer surface of the tablet while the purple layers represent the interfaces between the respective layers in the tri-layered tablet. Note the penetrative power of the THz pulse (penetration of > 3 mm into the tablet, THz pulse power < 5 μW).
The PSSRC