(260f) Exploring the Robustness of Terahertz-Based at-Line Porosity Measurements for Realising a Non-Destructive Dissolution Assay of Tablets during Manufacturing

Bawuah, P., University of Cambridge
Markl, D., University of Strathclyde
Farrell, D., TeraView Limited
Evans, M., TeraView Limited
Portieri, A., TeraView Limited
Lucas, R., Huxley Bertram Engineering Ltd
Zeitler, A., University of Cambridge


To achieve a continuous downstream manufacturing process with in-process quality monitoring and real-time release testing capabilities, different process analytical technologies (PATs) such as laser scattering methods, near infrared (NIR) spectroscopy, and Raman spectroscopy can be deployed to, for example, measure the particle size of raw materials and powder blends as well as to detect the content uniformity of powder blends and tablets. However, the use of the above-mentioned PAT methods to directly measure and quantify the bulk properties of tablets, e.g. porosity, that govern the mass transport processes and mechanical changes in tablets during disintegration and dissolution, are limited. For example, NIR methods to quantify tablet hardness typically probes surface properties only and these measurements are not necessarily representative of the bulk tablet property, hence the need for suitable analytical technologies, such as terahertz time-domain spectroscopy (THz-TDS), that can reliably measure the porosity in transmission of tablets [1, 2]. The total porosity, f, is a more meaningful metric to measure in order to predict the dissolution performance of the tablet as it can be directly linked to the mass transport of liquid into the tablet during disintegration through physical models whilst also being predictive of the mechanical strength of the tablet (f ∝ 1/ρ, with ρ density).

We recently developed a terahertz spectroscopy method to directly measure tablet porosity without the need for any chemometric model [1-4]. This study showcases the robustness of this method for measuring tablet porosity for a range of geometries and formulations, specifically several batches of flat and biconvex tablets with either ibuprofen or indomethacin as the active pharmaceutical ingredient (API). The study further investigates the effect of debossing on the extracted terahertz porosity. To explore the suitability of the method for possible in-line application we determined the interplay between signal averaging and error in porosity in order to determine the minimum measurement time using present commercial terahertz spectroscopy equipment. Finally, we investigate the correlation between porosity measured by terahertz spectroscopy and the mean dissolution time of immediate release tablets.


Several batches of flat and biconvex tablets with different porosities within the range of 6 - 25% were directly compressed using a compaction simulator (HB50, Huxley Bertram Engineering Ltd, UK). The production-scale tablet press (Fette 2090 B) compression profile, with a compression speed of 60 rpm, was used for compressing all the batches. The targeted porosity for each batch was achieved by keeping the weight of all tablets at 400 mg and adjusting their thickness. The formulation used was composed of microcrystalline cellulose (39.1% w/w), lactose anhydrous Supertab21AN (46.9% w/w), croscarmellose sodium (3.0 %w/w), Magnesium stearate (1.0% w/w), and ibuprofen/indomethacin (10.0% w/w). The proportions of the various powders were weighed and properly mixed using a Turbula mixer, T2F (Willy A. Bachofen AG, Switzerland). The blending process lasted for 11 mins with a speed of 32 rpm. Terahertz time-domain measurements of all the batches were acquired using a TeraPulse 4000 (TeraView Ltd., Cambridge, UK). The porosity was extracted from the measured terahertz effective refractive index using Bruggeman’s effective medium theory [1,5].


The comparison between the terahertz porosity values measured from the debossed tablets and those without debossing showed that the presence of the debossing has a negligible effect on the results. Both flat-faced and biconvex tablets exhibited an excellent linear correlation between the nominal and the terahertz porosity. Our results show the robustness of the terahertz approach for tablet porosity measurement over a wide range of geometries. We also observed that the root mean squared error (RMSE) of the linear correlation between the nominal and measured porosity stayed < 0.65% even when reducing the signal averaging to less than one second (for comparison one minute acquisition time results in a RMSE of around 0.4%). The equipment available today therefore would be suitable for at-line porosity measurements with a potential throughput of 1 tablet per second and future improvements to the terahertz equipment appear to make on-/in-line applications possible. Finally, an excellent correlation was observed between the porosity and the mean dissolution time, which highlights the suitability of this method for non-destructive prediction of the dissolution behaviour of pharmaceutical tablets during manufacturing.

ACKNOWLEDGEMENTS: The authors would like to thank Innovate UK (Project 5804) for the funding provided.


  1. Bawuah, P.; Pierotic Mendia A.; Silfsten, P.; Pääkkönen P.; Ervasti, T.; Ketolainen, J.; Zeitler, J.A. and Peiponen, K.E. Detection of porosity of pharmaceutical compacts by terahertz radiation transmission and light reflection measurement techniques. Int. J. Pharm. 465, 70-76 (2014).
  2. Bawuah, P.; Silfsten, P.; Ervasti, T.; Ketolainen, J.; Zeitler, J.A. and Peiponen, K.E. Non-contact weight measurement of flat-faced pharmaceutical tablets using terahertz transmission pulse delay measurements. J. Pharm. 476, 16-22 (2014).
  3. Markl, D.; Strobel, A.; Schlossnikl, R.; Bøtker, J.; Bawuah, P.; Ridgway, C.; Rantanen, J.; Rades, T.; Gane, P.; Peiponen, K.-E. and Zeitler, J. A. Characterisation of pore structures of pharmaceutical tablets: A review. J. Pharm. 538, 188-214 (2018).
  4. Markl, D.; Sauerwein, J.; Goodwin, D.J.; van den Ban, S. and Zeitler, J. A. Non-destructive determination of disintegration time and dissolution in immediate release tablets by terahertz transmission measurements. Res. 34, 1012-1022 (2017).
  5. Markl, D.; Wang, P.: Ridgway, C.; Karttunen, A-P.; Chakraborty, M.; Bawuah, P.; Pääkkönen, P.; Gane, P.; Ketolainen, J.; Peiponen, K.-E. and Zeitler, J. A. Characterization of the Pore Structure of Functionalized Calcium Carbonate Tablets by Terahertz Time-Domain Spectroscopy and X-Ray Computed Microtomography. Pharm. Sci. 106, 1586-1595 (2017).