(M1330-01-03) Formulation Testing of TiO2-Free Film Coating Alternatives from Three Film Coat Vendors

Purpose: Titanium dioxide (TiO2) is a widely used opacifier in pharmaceutical film coatings. In 2016, rat inhalation study carcinogenicity data increased scrutiny over using TiO2 in the food / pharmaceutical industries [1, 2, 3, 4]. In January 2020, the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) banned TiO2 in food [5]. Late 2021, the European Commission removed TiO2 from the EU list of approved food additives [6]. The Commission committed to review the maintained use of TiO2 in medicinal products before April 2024 [7]. If TiO2 use in pharmaceuticals is banned, products could meet registration challenges, making this investigation crucial. Thus, we sought to understand the EU TiO2 regulatory landscape, identify TiO2-free (TF) coat alternatives, and perform film coating evaluations on available TF coats. The project’s purpose was to evaluate critical quality attributes and processibility of tablets coated with TF alternatives to obtain an understanding of which TF coats could yield similar performance to current TiO2 film coats.

Methods: Five TF coating alternatives, Coats A – H (Table 1), were selected for initial evaluation. Coating studies, performed on placebo tablets, investigated combinations of vendor, opacifier (TiO2, Calcium Carbonate (CaCO3), or Magnesium Carbonate (MgCO3), and polymer (Polyvinyl Alcohol (PVA) or Hydroxypropyl Methylcellulose (HPMC)). Objectives included evaluation of the a) reconstituted coating suspension viscosity, b) minimum weight gain required for TF coats to achieve opacity, c) ability of TF coats to color match with TiO2 reference coats, and d) TF coat’s processability. Coats were resuspended in deionized water at a 20% wt/wt ratio. Viscosity was measured using an analog Brookfield LV Viscometer and its LV Spindle Set. Coating was performed using a Vector LDCS-3 HI-COATER®. Process parameters (0.5 L pan size, a 280 g batch size, and a 45C bed temperature) were kept consistent across batches, and tablet samples were pulled at pre-determined time points during the coating process to observe tablets with different weight gains ranging from 1 – 7%, correlating with 0.016 – 0.115 mg/mm².

Results: Suspension viscosity was measured prior to each coating run. Coats A, B, D, F, G, and H had acceptable viscosity (70.5 cP – 260.3 cP) under the desired 350 cP limit. Coat C’s viscosity exceeded the desired limit at 426.7 cP. Coat E was very viscous (2136.7 cP) and required a larger tubing size during processing. The spray rate was customized for each film coat’s viscosity (Figure 1). The weight gain samples were pulled at the same time points. Coats B and C (Vendor1) achieved tablet opacity at 4.9% and 3.5% weight gain, respectively, with Coat B more closely matching the TiO2 reference’s 4.8% weight gain. Coat E (Vendor2) achieved tablet opacity at 10.7% weight gain, nearly triple the reference’s 4.0% weight gain. Vendor3’s TF coats performances varied based on opacifier. Its CaCO3 coat (Coat G) achieved tablet opacity at 4.5% weight gain, nearly a percent lower than its TiO2 reference, while its MgCO3 coat (Coat H) did not achieve tablet opacity even at a 10% weight gain. Due to the varied spray rate between runs (~4 to ~9 g/min) the weight gain of samples pulled at each time point slightly deviated from the expected theoretical weight gains in the sampling plan. For all coats, excluding Coats E and H, sufficient opacity and tablet coverage was attained by the 7-minute time point, averaging about 4.0% weight gain. When compared to the TiO2 reference coat, the TF tablet color should be medium blue with no tablet defects and no processing concerns. Coat B had a slightly speckled appearance and more vibrant blue with no processing issues, and Coat C had a close color match with slight processability concerns. Coat E presented a light blue color and tablet defects. Both Vendor3’s coats had sub-optimal performance for color matching and processability due to sticking, which could be attributed to a spray rate limitation of the coats. Coat G’s tablets were mottled and a vibrant blue color. Coat H’s tablets were highly mottled and dark violet.

Conclusion: Each TF coat’s performance was benchmarked by its suspension characteristics, minimum tablet weight gain for opacity, and processability (Table 2). Vendor1’s TF coats, Coats B and C, were most suitable for future exploration, demonstrating TF coats are viable alternatives at similar solids loading, weight gain, and process parameters when compared to their TiO2 references. Coats E, G, and H presented coating system limitations related to either the maximum % suspension solids content or an upper spray rate boundary, which lead to high suspension viscosity or tablet sticking, respectively, and thus required higher weight gains for opacity. Though spray rates varied between coats, the information obtained from these studies was valuable to determine leading TF film coats. This work is beneficial as it provides key information to industry stakeholders by documenting the initial development work performed on novel TiO2-free film coats.

References: Lee KP, T. H. (1985). Pulmonary response of rats exposed to titanium dioxide (TiO2) by inhalation for two years. Toxicol Appl Pharmacol, Toxicol Appl Pharmacol.
2 Heinrich U, F. R. (1995). Chronic Inhalation Exposure of Wistar Rats and two Different Strains of Mice to Diesel Engine Exhaust, Carbon Black, and Titanium Dioxide. Inhalation Toxicology, 7(4):53.
3 F., P. (2005). Carcinogenicity study with nineteen granular dusts in rats. Eur J Oncol., 10, 249-81.
4 EFSA Journal 2016;14(9):4545.
5 USDA Foreign Agricultural Service. (2019). “France Bans Titanium Dioxide in food products by January 2020”. USDA
6 Draft. European Commission Regulation (EU)…amending Annexes II and III to Regulation (EC) No 1333/2008….as regards the food additive titanium dioxide (E 171). Pg. 2, Item (12). Officially adopted on 14 Jan 2022. Link to adoption announcement: Daily News 14 / 01 / 2022 (europa.eu)
7 The European Commission (2021). “DRAFT Commission Regulation (EU) 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 (E171)”. 2021

Acknowledgements: Thank you to the Vendors who contributed materials for these studies.