(W1030-12-82) Navigating Titanium Dioxide Free Coating Systems: Evaluating the Risk and Understanding the Alternatives

Purpose: Titanium dioxide (TiO2) has been generally regarded as safe (GRAS) by the US FDA and is a global pigment or excipient in various pharmaceutical products, owing to aesthetic properties such as whiteness or ability to provide uniform appearance when combined with other colorants. Use of colorants enhances product identification/differentiation for patients. TiO2 has functional properties due to high refractive index providing improved opacity (hiding power) and photostability for light sensitive compounds. TiO2 has been a key component in available coating systems. However, in 2022, European Commission banned use of TiO2 as food additive and encouraged pharmaceutical companies to find replacements. The potential ban of TiO2 use in pharmaceuticals has accelerated research to evaluate alternative TiO2 Free (TF) opacifiers, however a simple 1:1 replacement is suboptimal. While the replacement of TiO2 in coatings brings new risks due to new materials and potential for higher coating amounts, but in many cases, the coatings manufacturing process and product performance is acceptable. This current study was conducted to understand the challenges associated with using TF tablet coatings to deliver results like the TiO2 based coating and the adjustments required to address those challenges. The study evaluated the performance of TF coating against the TiO2 coating in terms of color development, color uniformity, surface roughness, dissolution, chemical, photostability and simulated shipping tests.

Methods: For TF coating, rice-starch based Opadry® 277U TF Yellow film coating was used while for TiO2 based coating Opadry® 05B Yellow TiO2 film coating. The coating suspensions were prepared in accordance with the manufacturer’s guidelines. For each coating system, 400 mg oval tablets were coated to a theoretical weight gain (4% for TiO2 based coating and 6% for TF coating) using Freund Vector LDCS-5 Pan coater using 1.3 L pan. Colorimetry was performed using datacolor Spectro 1000 X colorimeter to evaluate the color uniformity of the coated tablets. KEYENCE VHX digital microscope was used to evaluate coating thickness on tablet face and bands for assessing coating uniformity. Surface roughness, an important characteristic of the film coating which determines the aesthetic appeal of the coated tablets was also assessed using Keyence 5000 3D profiler for both TiO2 coated and TF coated tablets. Accelerated stability of the coated tablets were performed to assess photostability and package stability evaluating the influence of TF coating. Additionally, shipping simulation test was performed using Resodyn to simulate real life conditions at 3G acceleration, 60.05 Hz Frequency and 15% Intensity. Sink dissolution profiles of the TF coated tablets was compared to the TiO2 coated formulation with the fit for purpose USP 2 dissolution method using 0.5% SLS in 50mM sodium acetate pH 5.5 media with 50 rpm paddles followed by an infinity spin

Results: Tablets coated with Opadry® yellow TiO2 coating and Opadry® yellow TF coating displayed good visual color uniformity across the tablets (Fig.1a). One of the risks with new TF coatings is non-uniform color coating across various tablet location. The colorimetry data revealed uniform color coating on the band and face of the TF coated tablets with ΔE < 0.7 for all 6% coating weight gain. The Opadry® TF coating was not selected to provide an exact match to the Opadry® TiO2 coating yellow color, colorimetry data confirmed that higher coating weight gain (4% and 5%) for Opadry® TF coating was found to have ΔE < 0.4 when compared with 6% coating weight gain suggesting equivalent color comparison of the 4%, 5% and 6% coating weight gain. There were no tablet defects observed upon microscopic evaluation of the coated tablets as seen in Fig. 1b. Surface roughness was evaluated in terms of multi-line surface roughness and area surface roughness, results displayed low and comparable surface roughness for both Opadry® TiO2, and Opadry® TF coated tablets as seen in Fig. 2a. and Fig. 2b. While photostability is expected to be a challenge for TF coating systems, photostability results of the Opadry® TF coated tablets demonstrate good photostability suggesting the ability of new TF coatings to provide protection from light in some cases. Shipping simulation results confirmed the ability of Opadry® TF coating providing protection. Results of the dissolutions studies (Fig. 2c) showed comparable release profile between Opadry® TF coated and Opadry® TiO2 coated tablets, suggesting no impact of TF coating on the release of drug from these tablets.

Conclusion: Overall, TF coated tablets displayed low and comparable surface roughness and were found to be visually appealing and free of defects. Opadry® yellow rice-starch based TF coating system provided uniform color coating with ΔE < 0.7 at higher coating weight gain comparing 6% to 4% and 5%. Opadry® Yellow TF coating was successful in providing photostability at 6% weight gain. Shipping simulation study revealed ability of TF coating to provide physical protection like TiO2 coating. Dissolution profiles were found to be comparable for the TF coated and TiO2 coated tablets.

Figure 1: (a) Photographic images of tablets coated with Opadry® TF coating and Opadry ® TiO2 coating at various coating weight gain. (b) Microscopic images of the final weight gain tablets for Opadry® TF coating and Opadry ® TiO2 coating.

Figure 2: (a) Surface roughness profile of the Opadry® TF coated and Opadry ® TiO2 coated tablets along with representative optical image and 3D image of the coated tablets. (b) Surface roughness study parameters evaluated for the Opadry® TF coated and Opadry ® TiO2 coated tablet and (c) Dissolution results of both the coated tablets tested using USP 2 dissolution apparatus