The first paper discussing the uses of terahertz pulses in the pharmaceutical sector was published by Taday et al. in 2003 (1). This paper demonstrates that it was possible to identify polymorphs (Figure 1)of the drug substance in solid dosage forms with the help of terahertz pulsed spectroscopy. The limit-of-detection, showing that one polymorph can be measured in a mixture of another, was reported by Strachan et al.(2). As most dielectric materials are transparent in the terahertz region of the spectrum, it was soon realized that the terahertz pulses could be used to analyze the coating thickness on solid dosage forms(3,4). Unlike traditional microscopy measurements, the terahertz method provides the benefit of non-destructive assessment of coating thickness and other properties, preservingthe tablet for subsequent dissolution testing. This article outlines the techniques suitable for determining the coating thickness on tablets and correlating the thickness to wet dissolution.
A study based on this was conducted by Spencer et al.(5) who measured the coating thickness of mesalamine tablets using terahertz pulsed imaging and was then able to correlate to tablet dissolution. In a series of papers, Lo et al.(6,7,8) demonstrated the possibility of correlating the coating thickness as well as the coating density. Additionally, the raw terahertz pulse and chemometrics were used by Lo et al. in later work to predict the dissolution of sustained release pharmaceutical product(9). Figure 2 shows an example of correlation between the thickness on an enteric coated tablet and the dissolution. The outliners from the straight lines are a result of the imperfections existing in the tablet coating. In a recent paper, May et al. demonstrated a good correlation between the crushing force measured from compression tests and the refractive index measured by terahertz pulsed imaging using a set of tablets that were compacted at different compression forces, and this was found to be related tp tablet hardness(10). A terahertz sensor inside a coating pan was used by the same group to follow the build up of a pharmaceutical coating on a tablet(11).
Figure 1. Polymorphs of five common polymorphs of sulfathiazole (spectra off-set)
Figure 2. The coating thickness of enteric coated tablets is derived from terahertz pulsed measurements are correlated against the mean dissolution time for different coating weighs and levels of polymer (PEG). The black points have 12% PEG while the blue points have a PEG level of 9%. The outliner at x=4 minutes was due to a crack in the coating of the tablet.
A TeraPulse 4000 with robot module (TeraView, Cambridge, UK) was used to perform the 3D TPI measurements (Figure 3). The operation of this system has been well described before by Zeilter et al.(4). Images were obtained in a point-to-point mode with a step size of 200 µm.
3000 measurements were performed on each tablet, and the measurements for each tablet took almost 30 minutes. Images were taken by TeraView’s TeraPulse data analysis software and sample preparation was not needed. Source-generated terahertz radiation can penetrate 3 mm or more into a sample.
A reflection occurs whenever there is a change in the refractive index due to either a change in the tablets chemical or physical characteristics (Figure 4)
This is a ballistic reflection that occurs on the surface of the interfaces within a pharmaceutical product, and because of the finite speed of light that occurs at different times.
It is possible to use the time-of-flight capabilities of the technique to distinguish between pulses coming from different boundaries in the sample and randomly scattered photons.
It is also possible to obtain maps of the coating thicknesses of dosage form by measuring the differences between pulses arriving at different times – this can be done for multiple surfaces within the products and for the top surface. The tablet can be examined in three dimensions using the robot system. Figure 5 demonstrates the difference between 10% and 16% weight gain enteric coated tablets with solid loadings in the coatings mixture. The same color scale is used to plot the coating thicknesses on the tablets.
- Fault analysis of coating on production batches
- Product development of bilayer products
- Enhancing the performance of coatings on solid dosage forms
- The system has been used to solve production problems with polymer coatings and also in product development
Figure 3. Schematic diagram a TeraPulse 4000 with robotic system used to measure tablets.
Figure 4. Example of data obtained from the terahertz pulsed imaging method
Figure 5. Examples of tablets coated with 10% and 16% weight gain and different solid loadings in the coatings. The images are plotted on the same colour scale with red 250 microns and dark blue 50 microns.
- Taday PF, Bradley IV, Arnone DD, Pepper M. “Using Terahertz pulse spectroscopy to study the crystalline structure of a drug: a case study of the polymorphs of ranitidine hydrochloride” J Pharm Sci. 92(4):831-8 (2003)
- C.J. Strachan P. F. Taday, D. A. Newnham, K. C. Gordon, J. A. Zeitler, M. Pepper, T. Rades “Using terahertz pulsed spectroscopy to quantify pharmaceutical polymorphism and crystallinity”, J. Pharmaceutical Sciences, 94(4), 837-846 (2005)
- AJ. Fitzgerald, BE Cole and PF Taday, “Nondestructive analysis of tablet coating thicknesses using terahertz pulsed imaging”, J Pharm Sci. 94(1):177-83 (2005).
- Zeitler JA, Shen Y, Baker C, Taday PF, Pepper M, Rades T “Analysis of coating structures and interfaces in solid oral dosage forms by three dimensional terahertz pulsed imaging”, J Pharm Sci. 96(2):330-40 (2007).
- John A. Spencer, Zongming Gao, Terry Moore, Lucinda F. Buhse, Philip Taday, David A. Newnham, Yaochun Shen, Alessia Portieri, Ajaz Husain, “Delayed Release Tablet Dissolution Related to Coating Thickness by Terahertz Pulsed Image Mapping” J. Pharmaceutical Science 97(4), 1543-1550 (2008).
- Ho L, Müller R, Römer M, Gordon KC, Heinämäki J, Kleinebudde P, Pepper M, Rades T, Shen YC, Strachan CJ, Taday PF, Zeitler JA., “Analysis of sustained-release tablet film coats using terahertz pulsed imaging”, J Control Release. 119(3):253-61 (2007).
- Ho L, Müller R, Gordon KC, Kleinebudde P, Pepper M, Rades T, Shen Y, Taday PF, Zeitler JA, “Terahertz pulsed imaging as an analytical tool for sustained-release tablet film coating”, Eur J Pharm Biopharm. 71(1):117-23 (2009).
- Ho L, Müller R, Gordon KC, Kleinebudde P, Pepper M, Rades T, Shen Y, Taday PF, Zeitler JA “Monitoring the film coating unit operation and predicting drug dissolution using terahertz pulsed imaging” J Pharm Sci.;98(12):4866-76 (2009).
- Ho L, Müller R, Gordon KC, Kleinebudde P, Pepper M, Rades T, Shen Y, Taday PF, Zeitler JA “Applications of terahertz pulsed imaging to sustained-release tablet film coating quality assessment and dissolution performance” J Control Release. 127(1):79-87 (2008).
- Robert K. May, Ke Su, Lianghao Han, Shuncong Zhong, James A. Elliott, Lynn F. Gladden, Mike Evans, Yaochun Shen, J. Axel Zeitler J “Hardness and Density Distributions of Pharmaceutical Tablets Measured by Terahertz Pulsed Imaging” J. Pharm Sci 102:2179–2186 (2013)
- May RK, Evans MJ, Zhong S, Warr I, Gladden LF, Shen Y, Zeitler JA, “Terahertz in-line sensor for direct coating thickness measurement of individual tablets during film coating in real-time” J Pharm Sci. 2010 Oct 18 DOI: 10.1002/jps.22359
This information has been sourced, reviewed and adapted from materials provided by TeraView Ltd.
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