(W1030-08-53) Evaluation of Titanium Dioxide Alternative in Polymethacrylate (EUDRAGIT^® E PO) Based Coatings

Purpose: Titanium dioxide (TiO₂) has long been the primary opacifier in pharmaceutical coatings and cosmetics. However, recent regulatory scrutiny, particularly the European Union's classification of TiO₂ as a category-2 carcinogen (H351, inhalation), has raised safety concerns. This classification necessitates stringent labeling for products containing more than 1% TiO₂ with particle sizes under 10 µm, highlighting the urgent need for safer alternatives. This study aims to evaluate the performance of polymethacrylate based Immediate release (IR) coating system utilizing calcium carbonate (CaCO₃) as a substitute for TiO₂ and compare it with other TiO₂- and CaCO₃- based coating systems (polymethacrylate IR coating system (TiO₂-based) and HPMC-based coating systems using CaCO₃) regarding processing, opacity, disintegration, and dissolution characteristics.

Methods: Two types of tablet cores were prepared: black placebo tablets coated with ethyl cellulose and black iron oxide (for opacity evaluation), and caffeine tablets produced via wet granulation (for disintegration and dissolution studies). Coating dispersions were formulated for the polymethacrylate (EUDRAGIT® E PO) IR coating system based on TiO₂ and CaCO₃, as well as for the HPMC coating system based on CaCO₃. Each coating process utilized a perforated coating pan (Neocota, Neomachines) under recommended parameters. Opacity was assessed using a Spectrophotometer (SpectroEye X-Rite).  Disintegration tests were conducted using a USP apparatus across three media: water, pH 6.8 phosphate buffer, and 0.1N HCl. Dissolution profiles were evaluated in 0.1N HCl and pH 6.8 phosphate buffer using a USP Type 2 apparatus, with samples collected at specified intervals.

Results: The polymethacrylate-based coating system (utilizing TiO₂ and CaCO₃) demonstrated the capability to be processed at a higher solid content of 30% w/w with low viscosity, in contrast to HPMC-based formulations, which exhibited significantly higher viscosity at 20% w/w. Notably, the processing time for the polymethacrylate-based coating system was 1.5 times faster than that of the HPMC-based coating, a difference attributed to the higher solid content and lower viscosity of the polymethacrylate coating dispersions. The coating processes for both polymethacrylate based formulations were smooth, resulting in tablets with excellent gloss and texture. In comparison, HPMC-based coatings produced a rough surface with no gloss (as illustrated in Figure 1). Opacity analysis revealed that polymethacrylate-based IR coating system (TiO₂) achieved satisfactory opacity at 6% w/w coating build-up, while the CaCO₃-based formulations required slightly higher coating build up i.e. 8% w/w for the black core in order to achieve complete coverage over edges. All formulations maintained L-values above 94, indicating significant whiteness and comparable opacity. Disintegration times for all formulations were within 10 minutes across all media, meeting USP requirements. The dissolution profiles demonstrated that both the TiO₂ and CaCO₃-based polymethacrylate formulations, along with HPMC-CaCO₃ based coating system, provided fast and complete release within 30 minutes.

Conclusion: This study highlights the superior performance of polymethacrylate-based coating formulations over HPMC-based systems for immediate-release applications. The polymethacrylate IR coating system (TiO₂/CaCO₃ based) demonstrated enhanced workability with higher solid content, lower viscosity, and significantly faster coating process as compared to the HPMC-based coating system, resulting in tablets with excellent gloss and smooth texture. The direct comparison of TiO₂- and CaCO₃-based polymethacrylate formulations revealed the need of a higher coating build-up for CaCO₃-based coatings to achieve complete coverage of edges. These findings suggest that calcium carbonate can serve as an effective alternative to titanium dioxide in polymethacrylate-based immediate-release coatings offering significantly better performance as compared to the HPMC-based coating system.

References: 1. EUDRAGIT® Application guidelines, 13th edition.
2. New guide available on classifying and labelling titanium dioxide, ECHA/NR/21/23.

Fig 1: Comparison of appearance and opacity of polymethacrylate based IR coating system (TiO2- and CaCO3- based) and HPMC IR coating system (CaCO3- based)