PURPOSE

Tablet porosity is a critical quality attribute which controls key mass transport mechanisms that govern disintegration behaviour, and ultimately drug release and dissolution, in a number of widely used oral solid dosage forms [1]. This study demonstrates the use of TeraSolve, a newly developed at-line PAT tool based on transmission terahertz spectroscopy, that allows for the non-destructive measurement of tablet porosity and disintegration time within fractions of a second per tablet without any prior sample preparation [2]. At the example of a large sample from a commercially sourced batch of an immediate release (IR) drug product we investigate the distribution of tablet porosity within the batch and compare the results to the pharmacopeial quality expectations. Using this novel terahertz porosity sensing method, we are able to measure thousands of tablets, which allows us to gain a unique insight into the intra-batch quality distribution of the drug product and the ability to detect and track potential nonconforming tablets that fall outside the specified quality range and subject them to subsequent (destructive) quality testing to allow for better understanding why these samples exhibit anomalous quality characteristics.

MATERIALS AND METHODS

An initial study has been conducted on several hundreds of ibuprofen-based IR tablets that were compacted using a laboratory based rotary press (a YouTube video about the initial study is available from this link https://www.youtube.com/watch?v=XxvXSL_2TzM&t=31s). The current study is a continuation where we seek to apply the method on a large number of tablets (approximately 5,000) from a commercially sourced batch of doxycycline drug products. The thickness and porosity of all tablets will be simultaneously measured using the TeraSolve system (TeraView Ltd., Cambridge, UK). To predict and validate the disintegration time of the tablets based on the porosity measurements, a standard disintegration tester (DT50, SOTAX AG, Switzerland) will be used.

Our previous results from the laboratory based compressed IR tablets have demonstrated the ability of the newly developed at-line terahertz sensor, TeraSolve, to quantify subtle differences in tablets porosity and hence predict the disintegration performance. The current study intends to extend the above demonstration by measuring several thousands of commercially available IR drug products and investigate the distribution of disintegration behaviour typically encountered in a commercial product on the market.

CONCLUSIONS

It is the believe of the authors that the success of the proposed study will trigger a different dimension in the approach towards quality testing routines in the pharmaceutical industry. Quality testing based on sampling thousands of tablets is becoming increasingly feasible, which allows for obtaining a distribution on tablet quality and identifying nonconforming tablets from a batch during processing. The testing of larger number of samples from a population will allow to develop better process and product understanding, which will ensure safety and trust of pharmaceutical products by patients.

ACKNOWLEDGEMENTS: The authors would like to acknowledge the contributions of our partners from the University of Strathclyde, Heinrich-Heine-University, TeraView Limited, GlaxoSmithKline (GSK), and Huxley Bertram Engineering Limited during the initial studies.

REFERENCES

1. 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. Pharm. Res. 34, 1012-1022 (2017).
2. Bawuah P.; Markl D.; Turner A.; Evans M.; Portieri A.; Farrell D.; Lucas R.; Anderson A.; Goodwin D.J. and Zeitler J.A. A fast and non-destructive terahertz dissolution assay for immediate release tablets. J. Pharm. Sci. In press (2020).