Titanium dioxide (TiO₂), an inorganic chemical substance, has long been a crucial excipient in pharmaceutical tablets, serving as an opacifier and white colorant. However, recent developments have raised concerns about its safety and prompted a search for alternatives.
The European Union banned the use of titanium dioxide (grade E171) as a food additive in 2022 due to safety concerns. While this ban does not directly apply to pharmaceuticals, it has sparked discussions about the substance’s use in medications, especially given that the European Medicines Agency (EMA) estimates that approximately 91,000 human medicinal products contain titanium dioxide.
Recent studies in mice have raised potential health risks associated with TiO₂, including DNA damage and immune system toxicity. While it’s important to note that there is not yet strong evidence that TiO₂ is unsafe for humans when used in tablets, the possibility that it could face future restrictions looms large, leaving many pharma companies weighing their options.
Current Regulations
When the EU banned titanium dioxide as a food additive in 2022, it left open the possibility of extending the ban to pharmaceuticals. The European Commission is expected to give more clarity on the use of TiO₂ as excipient in drugs this year. Meanwhile, the EMA, the EU’s drug regulator, has warned that an immediate ban on TiO2 in medicine could lead to shortages.
International health agencies, including the U.S. FDA, Health Canada and the United Kingdom’s Food Standards Agency, have not agreed with the EU’s safety assessment. The FDA does not note concerns about the safety of TiO₂, requesting only that the quantity of titanium does not exceed 1% by weight of the food. In pharmaceuticals, the FDA regulates the use of TiO₂ as a color additive under 21 CFR 73.1575, provided that use complies with specific purity and safety standards.
The Hunt for Alternatives
Despite international disagreements over safety, the search for TiO₂ alternatives has intensifi ed, with scientists evaluating hundreds of alternative opacifiers as potential substitutes. Several suppliers have since developed TiO₂-free formulations for tablet film coatings.
One leading alternative is calcium carbonate (CaCO3), a naturally occurring mineral and one of few currently approved white drug colorants in the EU. When compared to other alternatives, CaCO3 offers superior light protection properties, which is important for stability and shelf life.
In a study that analyzed a number of different pigments coated on tablets, none of the alternative options showed comparable effectiveness and efficiency in terms of coating potential to TiO₂, however, the CaCO3 and dicalcium phosphate (CaHPO4)-based coating showed the second-best results. In that same study, zinc oxide was comparable to TiO₂ in terms of its ability to protect photosensitive active ingredients. Since exposure to light can degrade active ingredients and cause pigments to fade, photostability is a critical consideration when looking for alternatives.
Finding a replacement that exactly matches TiO₂’s safety, performance and supply chain reliability is an ongoing challenge. As regulatory bodies continue to assess the situation, pharma companies are smart to prepare for potential changes in TiO₂ regulations.
References
TiO2 EU Regulations and Pharmaceuticals: What to Know. Colorcon. Jan. 2023.
Blundell, R., et. al. The Role of Titanium Dioxide (E171) and the Requirements for Replacement Materials in Oral Solid Dosage Forms. J Pharm Sci. Nov 2022.
Estimated intake of titanium dioxide via medicines. RIVM on Advanced Materials. Dec. 2024.
Titanium Dioxide as a Color Additive in Foods, U.S. FDA. Accessed: Feb. 2025.
21 CFR Part 73. Code of Federal Regulations. Accessed: Feb. 2025.
Challenges and Opportunities to Formulate Nutraceutical Tablets Without Titanium Dioxide. Colorcon. March 2024
Radtke, J., et. al. Alternatives to titanium dioxide in tablet coating. Pharmaceutical Development and Technology. 2021.