The European Commission has banned the use of titanium dioxide (TiO2) in food products and dietary supplements and is awaiting an assessment by the European Medicines Agency to determine if a similar ban should be put into effect for medicinal products. Formulators should be considering alternatives today in order to prepare for the possible implementation of such a ban. Parteck® TA (Calcium carbonate) Emprove® Essential is a particle-engineered calcium carbonate (CaCO3) product in the MilliporeSigma’s SAFC® portfolio that was specifically developed as an alternative to TiO2 that can be used without impacting tablet performance.
A Multifunctional Ingredient
Titanium dioxide (TiO2) is extensively used as an opacifier and colorant in the food and pharmaceutical industries. In the food industry, TiO2 is a popular ingredient in chewing gum and candies that have a coated core. Colored coatings applied to an underlying TiO2 coating have more shine and are more brilliant.
In white oral solid dosage forms, the multiple functionalities of TiO2 make it an ideal excipient. Indeed, the European Medicines Agency estimates that approximately 91,000 human medicinal products, including both tablets and capsules, contain titanium dioxide.1 In addition to serving as an excellent white pigment, TiO2 acts as an efficient opacifier owing to its high refractive index, which effectively scatters light. As a result, this excipient provides excellent hiding power for pharmaceutical coatings and enables the protection of light-sensitive ingredients. Furthermore, the homogeneous appearance of tablets across different batches of tablets leads to improved medication adherence by patients compared with those tablets lacking an effective opacifier.
Potential European Ban Driven by Uncertainties
In the EU, the safe use of TiO2 in the food industry has been under scrutiny for some time. The focus has been on the potential harmful effects of TiO2 nanoparticles, with the assessment considering the results of nearly 10,000 studies, including some that had not previously been evaluated. Ultimately, the European Food Safety Authority (EFSA) was not able to conclude that TiO2 (referred to as E 171) is in fact genotoxic, but it could not rule out the possibility that titanium dioxide may have genotoxic effects either, concluding that the safety of the product cannot be confirmed.1 The end result was the adoption of Regulation (EU) 2022/63 by the European Commission withdrawing the authorization for TiO2 as an additive in foods and dietary supplements, which took effect in August 2022.2
For the time being, TiO2 remains on the list of color additives authorized for use in medicines. However, the commission is to re-evaluate the situation on the basis of an updated EMA assessment to be performed before April 2024. According to a statement by the EU Commission in January 2022, “… the pharmaceutical industry should make any possible efforts to accelerate the research and development of alternatives to replace titanium dioxide in both new and already authorized products.”3
While the quantities of TiO2 consumed in tablets and capsules is much less than what is found in many food products, the possibility remains that the use of TiO2 in drugs will also be banned. It is expected that any ban would be implemented in such a manner as to avoid supply disruptions that could impact patients, and a long transition period (e.g., eight years or more) could be expected.
Potential Worldwide Impacts
Regardless of ongoing reviews by other regulatory agencies, manufacturers must consider the practicality of producing different products for different markets. Supporting the production and distribution of different formulations for the U.S. and European markets, for instance, would involve significant effort and resources on the part of drug makers. Consumer concerns must also be factored in; the current ban in Europe applies to not only foods, but nutritional and dietary supplements, and customers may become wary of any products — including medicines — that contain TiO2. Consequently, there is general interest in finding TiO2 alternatives that provide a comparable performance so that only one product formulation will be needed for all markets going forward.
Formulators Need to be Prepared
Based on the Commission’s statement from January 2022,3 it is expected that the EMA will provide an updated assessment by April 2024, with a final decision regarding the use of TiO2 as an excipient in pharmaceutical products to be made public sometime in early 2025. Given that it is difficult to predict the outcome of the Commission’s final review, formulators would be wise to start evaluating possible TiO2 alternatives as a risk-mitigation strategy, if they have not begun to do so already.
Calcium Carbonate Alternative
From a regulatory perspective, calcium carbonate (CaCO3) can be seen as the next best alternative to TiO2. This pigment is the only other white colorant approved as a drug colorant in the EU. Other compounds are also under evaluation, such as magnesium carbonate. For formulators looking for an effective risk-mitigation strategy, however, calcium carbonate is the first choice owing to its current approval status in the EU.
While TiO2 offers outstanding opacity and makes it possible to achieve uniform tablet coatings for pre-colored tablet cores, not all tablets require such a high level of opacity. In addition, there are strategies for achieving comparable appearance with CaCO3, even in demanding applications with high pre-coloring levels. The lower refractive index of calcium carbonate means that a higher concentration of pigment may be needed. The engineering of CaCO3 particles provides another approach.
A Highly Engineered CaCO3 Alternative
Parteck® TA (Calcium carbonate) Emprove® Essential is a particle-engineered CaCO3 alternative that has the ideal morphology and particle size for enhanced opacity in tablet coating. Increased opacity depends on the ability of particles to scatter incident light, which is influenced by several factors, including the particle size, shape, surface features, and structural arrangement. The new Parteck® TA engineered CaCO3 excipient was designed with a unique and homogeneous morphology and particle size distribution for improved light scattering and reduced batch-to-batch variability (Figure 1). As a result, this new form of CaCO3 can serve as a viable alternative to TiO2 for tablet formulations.
Scanning Electron Microscopy Image
Importantly, Parteck® TA (Calcium carbonate) Emprove® Essential is compliant with Ph Eur, BP, USP, E170, and FCC requirements and has GRAS (generally recognized as safe) status. It also has excellent compatibility with commonly used pharmaceutical coating polymers, including hydroxypropyl methyl cellulose (HPMC) and polyvinyl alcohol (PVA). Furthermore, the lower impact on the viscosity of spray liquids containing the new Parteck® TA CaCO3 allows higher pigment concentrations and thereby enables highly efficient coating processes with this excipient. Emprove® documentation, meanwhile, facilitates the qualification, risk assessment, and process optimization of formulations containing the new calcium carbonate excipient.
No Effect on Tablet Performance
Any time a drug product must be reformulated, regardless of the reason driving the use of alternative ingredients, the new formulation should exhibit comparable performance to the original. Benchmarking studies were therefore conducted to demonstrate and confirm that the engineered Parteck® TA CaCO3 excipient provides performance similar to that of formulations with TiO2. Its performance was also compared to that of other CaCO3 products on the market.
These studies revealed that use of Parteck® TA does not affect tablet performance. In addition to exhibiting low water uptake, it affords good stability. In comparison to TiO2-containing films, a similar coverage was observed for formulations with the Parteck® TA excipient when applied in a film formulation over white and black cards in a screening test, as well as for simulated pre-colored tablets by using higher concentrations of Parteck® TA. A proprietary in-house method based on the CIELab color system was used to determine lightness and whiteness. Generally, higher concentrations of Parteck® TA excipient and CaCO3 are required for some cases to achieve the same level of opacity and brightness provided by TiO2. That results in a weight gain of typically 5–8% depending on the formulation.
Synergistic Parteck® Coating Portfolio
Parteck® TA (Calcium carbonate) Emprove® Essential joins a comprehensive portfolio of excipients within MilliporeSigma's SAFC® Pharm/BioPharm raw materials portfolio that are particle-engineered to provide specific functionality. The new CaCO3 excipient is highly compatible with other SAFC® coating-related products, including plasticizers, anti-tacking agents, emulsifiers, other pigments, and the PVA-based coating agent Parteck® COAT.
Notably, for formulations containing Parteck® TA in combination with Parteck® COAT polymer, an even increased opacity can be achieved compared with standard HPMC-coating formulations.
Extensive Application Services
A key conclusion drawn based on results obtained for the new Parteck® TA excipient is that the composition of the coating has to be tailored to the respective tablet core formulation, which is why application know-how is key for success when substituting TiO2 with particle-engineered CaCO3.
MilliporeSigma's SAFC® Pharm/BioPharm raw materials portfolio is well positioned to help formulators in this area. In addition to providing access to the company’s broad coating ingredient portfolio, MilliporeSigma has experts with extensive application experience who are ready to support formulators with the development of new drug products that are TiO2-free, including the design of film coatings. Working in partnership with customers, MilliporeSigma’s expert formulators are able to help understand the specific needs for a given formulation, guide the selection of appropriate CaCO3 concentrations, and provide customers with tips and tricks for applying the suitable formulations once they are developed.
References
- Final feedback from European Medicine Agency (EMA) to the EU Commission request to evaluate the impact of the removal of titanium dioxide from the list of authorised food additives on medicinal products. European Medicines Agency, 8 September 2021.
- Commission Regulation (EU) 2022/63 of 14 January 2022 amending Annexes II and III to Regulation (EC) No 1333/2008 of the European Parliament and of the Council as regards the food additive titanium dioxide (E 171) (Text with EEA relevance). European Commission, 14 January 2022.
- Re-evaluation, “Questions & Answers on titanium dioxide.” European Commission, 2022.