(T1130-05-26) Iron Oxides in Titanium Dioxide-Free Coatings Protect Photolabile Active Pharmaceutical Ingredients in Oral Solid Dosage Forms

Purpose: In January 2022, the European Commission adopted a ban of Titanium Dioxide (TiO₂, E171) in food products. This was largely based on an assessment by the European Food Safety Authority (EFSA) stating that TiO₂ can no longer be considered safe due to concerns of genotoxicity. Currently a temporary provision includes E171 as an approved colorant for medicines, however, the Commission will review and decide on allowing the continued use of TiO₂ in medicines by February 2025. Although Titanium Dioxide is ubiquitous in tablets and capsules for oral use as an opacifier and colorant specifically to enhance the appearance and photostability of active pharmaceutical ingredients (API), there is a need to identify alternatives which offer similar or greater photoprotection to photolabile APIs.^1,2 Here, we demonstrated the use of iron oxides (FeO) in a high opacity TiO₂-free film coating as a promising alternative.

Methods: A blend containing a model photosensitive drug substance was mixed with standard pharmaceutical excipients and compressed into 500 mg round tablet cores. High opacity TiO2 free coating formulations were supplied by a contract manufacturing organization and were prepared using different quantities and combinations of red, yellow, and black iron oxides following the design of a response surface experiment. Tablets were coated with these coating formulations up to 8% weight gain using an O’Hara Labcoat Benchtop Tablet Coating System. Coated tablets, tablet cores (positive control), and tablet cores covered by foil (negative control) were placed into a Ametek Atlas Suntest CPS+ photostability chamber for photostability testing following ICH Q1B guidelines. These tested samples were analyzed using UPLC and the amount of API remaining and the photodegradant formed were measured.

Results: Tablets containing the model photosensitive drug substance in the TiO₂-free high opacity coating without iron oxides do not exhibit a high level of photoprotection when tablets are exposed to direct light (Figure 1). Even when this coating was applied to an 8% weight gain, similar rates of degradation occurred. The TiO₂-free high opacity coating formulated with 2-8% Red FeO and coated with a 4% theoretical weight gain resulted in practically no photodegradation from the ICH light box test (Figure 2). Ongoing experiments are exploring lower concentrations of iron oxide that will show the minimum level of iron oxides needed to prevent photodegradation. Surface plots describe the relationship between iron oxide concentrations and percent degradation. Finally, a potential color palette for photolabile compounds based on the optimal iron oxide levels will be presented from this DOE.

Conclusion: Iron oxides demonstrate strong potential to provide photostability (in the absence of titanium dioxide) in film coatings for tablets. In this study, the high opacity TiO₂-free coating with iron oxide coated at 4% weight gain was nearly equal to the tablet core covered in foil. The extent of the color palette is determined by the range of iron oxide levels that offer photoprotection.

References: 1 Blundell, Ross et al. “The Role of Titanium Dioxide (E171) and the Requirements for Replacement Materials in Oral Solid Dosage Forms: An IQ Consortium Working Group Review.” Journal of pharmaceutical sciences vol. 111,11 (2022): 2943-2954. doi:10.1016/j.xphs.2022.08.011
2 Hancock, Bruno et al. “Titanium Dioxide (E171 Grade) and the Search For Replacement Opacifiers and Colorants: Supplier Readiness Survey, Case Studies and Regulatory Perspective.” Journal of pharmaceutical sciences vol. 113,5 (2024): 1285-1298. doi:10.1016/j.xphs.2023.12.006


Figure 1. Tablet coatings without iron oxide up to 8% weight gain.


Figure 2. Tablet coatings with red iron oxide up to 8% weight gain.