In-Line Monitoring Approach for Titanium Dioxide-Free Tablet Coatings Developed at TU Dortmund University

In a recent study conducted by researchers from TU Dortmund University in Germany, the researchers looked at how to improve the safety of tablet coatings on pharmaceutical drugs. Titanium dioxide, a common coating component, has concerned drug manufacturers and the scientific community because of its potential carcinogenicity (1). In their study, the research team demonstrated a novel in-line monitoring method for titanium dioxide-free tablet coatings, marking a significant step forward in pharmaceutical manufacturing, using calcium carbonate as a substitute (1).

Pharmaceutical tablets are solid unit dosage forms that is comprised of a mixture of substances and excipients (2). Approximately two-thirds of all prescription drugs come in tablet form (2). The most common pharmaceutical tablets often are produced as either coated or uncoated. Coated tablets contain an additional coating layer, which is designed to mask taste and color, control the release profile of the drug, to enhance stability, or both (2). Coating also helps prevent tablets from sticking together when being processed and packaged while improving the mechanical strength of the dosage (3). Uncoated tablets have at least one layer of formulation that consists of active ingredients and excipients compressed together (1).

Pharmacy theme, white medicine tablets antibiotic pills. | Image Credit: © zadorozhna - stock.adobe.com

For coating tablets, titanium dioxide has routinely been used for this purpose because of its opacity. However, due to its associated health risks, calcium carbonate is increasingly being considered as a safer alternative (1). Although calcium carbonate shares the opacity characteristics of titanium dioxide, its Raman spectrum exhibits overlapping peaks with carbon hydrates, which complicates accurate measurement using traditional monitoring methods (1).

The research team sought to address these challenges. To do so, the team investigated using two advanced modeling techniques for in-line monitoring: partial least squares regression (PLS) and complemental hard modeling (CHM) (1). The goal was to evaluate the efficacy of these models in predicting the mass growth of the coating material on tablets while assessing how different probe positions in the coater could affect model performance (1).

In the study, tablets were coated in a KOCO 25 semi-continuous coater with a coating solution containing calcium carbonate. The research team compared two Raman probe measurement positions: orthogonal (at the nozzle arm) and tangential (on the back wall of the coater, measuring the moving tablet bed) (1). The probes collected spectral data during the coating process, which was then analyzed using the PLS and CHM models. The evaluation of these models showed promising results, with both demonstrating the ability to predict coating mass growth with comparable accuracy (1). The root mean square error of cross-validation (RMSECV) values were approximately 5% for both models, indicating a good fit with the data (1).

Comparing both approaches, the researchers found that the CHM model outperformed PLS. CHM, which is based on a mechanistic structure that adjusts component weights by solving least squares problems, proved to be more robust in handling lower-quality data (1). This enhanced performance makes CHM a compelling alternative for in-line monitoring of tablet coatings, especially when fewer data points are available for training (1).

Furthermore, the study revealed that the choice of probe position did not significantly impact the accuracy of the models. Both orthogonal and tangential measurement positions provided sufficient exposure time for accurate data collection, with the orthogonal position yielding slightly better model evaluation parameters (1).

In conclusion, the researchers demonstrated in their study that both PLS and CHM are suitable for in-line monitoring of titanium dioxide-free tablet coatings, with CHM offering enhanced performance in situations with reduced data quality and quantity (1). These findings provide valuable insights for the pharmaceutical industry, particularly as manufacturers look for safer, more sustainable alternatives to titanium dioxide in tablet coatings.

References

1. Brands, R.; Bartsch, J.; Thommes, M. Complemental Hard Modeling in Raman Spectroscopy: A Case Study on Titanium Dioxide-free Coating In-line Monitoring. J. Pharm. Sci. 2025, 114 (1), 577–585. DOI: 10.1016/j.xphs.2024.10.044
2. LFA Tablet Presses, Types of Tablets. LFA Tablet Presses. Available at: https://www.lfatabletpresses.com/articles/type-of-tablets#:~:text=Uncoated%20%E2%80%93%20a%20single%20layer%20or,%2C%20sugar%2C%20plasticizers%20and%20waxes. (accessed 2025-01-15).
3. Salawi, A. Pharmaceutical Coating and Its Different Approaches, A Review. Polymers (Basel.) 2022, 14 (16), 3318. DOI: 10.3390/polym14163318