Wednesday, 08 October 2014 00:00

Improved Process Understanding of Tablet Film Coating

Written by Hungyen Lin
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Layer thickness maps of the individual tablets faces showing intra-tablet coating uniformities and response to process conditions Layer thickness maps of the individual tablets faces showing intra-tablet coating uniformities and response to process conditions


Terahertz pulsed imaging (TPI) was first introduced in 2007 to non-destructively measure the coating thickness of pharmaceutical tablets. Ever since then, there has been a concerted research effort throughout the PSSRC to further develop and exploit this technique for improving the quality of pharmaceutical coatings and to shed light on the intricacies behind the pharmaceutical tablet coating process.

A notable example of previous work is the use of TPI to monitor the growth of the coating layer during the coating process as an offline technique [1]. The technology was further developed as an inline modality, where unlike the more established techniques such as near-infrared and Raman spectroscopy, TPI could measure coating thickness of individual tablets directly without chemometric models and was able resolve the tablet-to-table thickness distribution inside the coating drum during the coating process [2]. This makes the terahertz technique a unique tool to investigate the microstructure of pharmaceutical tablets as discussed in a previous research highlight.

Validation and Application

In TPI the only material dependent variable that needs to be calibrated in order to measure absolute film thickness is the refractive index of the coating material. The refractive index at terahertz frequencies is different to that at visible frequencies and while it is possible to measure it using terahertz spectroscopy it is important to validate these measurements using an independent technique. In an effort to further demonstrate the applicability of TPI, the method was validated with x-ray microtomography [3] to confirm the assumption that the refractive index is constant, within acceptable error, across the tablet surface for quantifying the absolute coating thickness (Figure 1).

TPI was also demonstrated to quantify active coating processes with active coatings up to 500 µm thick [4]. The applicability of TPI was further shown to work hand in hand with existing techniques, especially as a reference technique in the development of chemometric coating models for in-line Raman spectroscopy of process monitoring and quantification of functional coats [5].

In order to bring users up to speed when using TPI in the context of quantitative pharmaceutical tablet measurement and data analysis, a recent paper [6] presented an extensive discussion on the relevant parameters that need to be controlled so as to not fall into the trap of misinterpreting the TPI measurements. Of a particular mention in this context is the case where active coating is applied to tablets. Interestingly, the refractive index of the active coating was found to change in response to certain process conditions leading to measurement uncertainties when determining the absolute coating thickness. By comparing the content measurements as measured by an HPLC assay and the TPI coating thickness measurements it was possible to establish an excellent correlation between the TPI coating thickness measurement and the drug content in the coating (Figure 2).

Process Understanding

A high level of intra-tablet and inter-tablet coating uniformity are desired attributes in the pharmaceutical film coating process. This is especially the case for tablets receiving functional coats such as sustained release formulations, where a high level of coating variability can potentially undermine the efficacy of the eventual drug product. Even though these attributes are well sought after in the industry, achieving them realistically may prove to be rather difficult.

To date, only a handful of investigations have aimed to identify the process conditions that reliably lead to a reduction in coating thickness variability. TPI, owing to its relatively high spatial resolution, has shown to be a suitable tool for quantifying active coating thickness uniformity of tablets coated under varying process conditions [7, 8]. In particular, using design of experiments (DoE) covering a wide range of realistic coating process conditions for process parameters such as drum load, drum rotation speed, spray rate, spray pressure and coating duration, TPI was used to non-destructively identify and optimise the critical process parameters for an active coating process (Figure 3 and 4). Specifically, it was found that low drum load, high drum rotation speed and long coating durations are factors that could improve intra-tablet and inter-tablet uniformity. Even though a low spray rate was shown to be beneficial for inter-tablet coating uniformity, the same setting would be counter-productive in reducing the level of intra-tablet coating uniformity.

One immediately obvious advantage of the TPI technique for the analysis of active coating processes in this context is the speed and ease of measurement compared to an HPLC content assay: no sample preparation is required, no solvents are used and need to be disposed of and each measurement is completed in well under one hour.


In light of recent developments, TPI has further proven to be a robust technology in the field of pharmaceutics with particular advancements made in investigating active coating processes. While the relative immaturity and stability limitations of the technology are barriers for industry-wide adoption, TPI has shown tremendous potential in studying the coating uniformities non-destructively that otherwise would have been difficult to perform, if not impossible, with the existing popular techniques. Future implementations of the TPI as an in-line tool can effectively resolve the inter-tablet inhomogeneities during the coating operation as previously shown [2] and real-time information can be acquired for in-depth process understanding leading to greater control of the process for the production of higher quality dosage forms.


[1] 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, Analysis of sustained-release tablet film coats using terahertz pulsed imaging, J. Control. Release 119, 253 (2007),

[2] R. K. May, M. J. Evans, S. Zhong, I. Warr, L. F. Gladden, Y. Shen, and J. A. Zeitler, Terahertz in-line sensor for direct coating thickness measurement of individual tablets during film coating in real-time, J. Pharm Sci. 100, 1535 (2011),

[3] I.-S. Russe, D. Brock, K. Knop, P. Kleinebudde, and J. A. Zeitler, Validation of Terahertz Coating Thickness Measurements Using X-ray Microtomography, Mol. Pharm. 9, 3551 (2012),

[4] D. Brock, J.A. Zeitler, A. Funke, K. Knop, and P. Kleinebudde, A comparison of quality control methods for active coating processes, Int. J. Pharm., 439 (1-2) (2012), 289-295

[5] J. Müller, D. Brock, K. Knop, J. A. Zeitler, and P. Kleinebudde, Prediction of dissolution time and coating thickness of sustained release formulations using Raman spectroscopy and terahertz pulsed imaging, Eur. J. Pharm. Biopharm. 80, 690 (2012),

[6] D. Brock, J.A. Zeitler, A. Funke, K. Knop, and P. Kleinebudde, Critical factors in the measurement of tablet film coatings using terahertz pulsed imaging, J. Pharm. Sci., 102, 1813–1824 (2013),

[7] D. Brock, J.A. Zeitler, A. Funke, K. Knop, and P. Kleinebudde, Evaluation of critical process parameters for intra-tablet coating uniformity using terahertz pulsed imaging, Eur. J. Pharm. Biopharm., 85, 1122-1129 (2013),

[8] D. Brock, J.A. Zeitler, A. Funke, K. Knop, and P. Kleinebudde, Evaluation of critical process parameters for inter-tablet coating uniformity of active-coated GITS using terahertz pulsed imaging, Eur. J. Pharm. Biopharm. (2014).

PSSRC Facilities

The group of Dr Axel Zeitler at Cambridge has extensive experience with terahertz 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.

Professor Peter Kleinebudde’s group in Dusseldorf has a range of film coating equipment and process experience that can be used to simulate realistic process conditions during pharmaceutical film coating. In addition there is a wide range of expertise on film coating of tablets and pellets within the cluster in the centres in Copenhagen, Ghent and Lille.

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