(T1330-08-48) Titanium Dioxide Free Color Mixtures for Use in Pharmaceutical Drug Products: A Manufacturing Performance Evaluation of the Alternatives

Purpose: Titanium dioxide (E171) is an excipient used in ready-made coating systems to facilitate the identification for solid oral dosage forms by ensuring homogeneity of appearance. In addition to identification of the tablet, the use of titanium dioxide in the tablet coating disperses visible and ultraviolet light so the drug substance in the tablet core is protected from light. In January 2022, the European Commission banned the use of E171 in foods but allowed for it to provisionally authorized for use in medicinal product while the pharmaceutical industry makes any possible efforts to accelerate the research and development of alternatives.¹ In an effort to understand the challenges associated with the current titanium dioxide free ready-made coating systems, an assessment was performed evaluating the impact these systems have on the coating process along with appearance, uniformity of color and ability to maintain a pharmaceutically elegant dosage form.

Methods: Several ready-made coating systems were investigated in the assessment of substitutes for titanium dioxide. The systems mirrored historically acceptable coating formulations of customary colors. Differences in the color mixtures utilized calcium carbonate and a combination of calcium carbonate and isomalt, a component that offers a synergistic opacifying effect with calcium carbonate, as replacements for titanium dioxide. The coating systems were evaluated in a study on a perforated coating pan. For each of the systems, 400 mg round, debossed, placebo tablets were coated to a weight gain up to ~9%. The coating suspensions for these studies were prepared and applied with close adherence to manufacturer’s guidance. Intermittent samples were removed at every ~1% theoretical weight gain. Following the completion of the coating trials, colorimetry testing based on CIELAB color space metrics was used to understand what weight gains provided acceptable color uniformity. Further testing was done using microscopy to evaluate the risk of logo bridging and coating thickness at various locations to look at coating uniformity.

Results: The coated tablet color from titanium dioxide free formulation were not an exact color match to their titanium dioxide counterparts for the coating systems studied. Colorimetry data from a coating system containing titanium dioxide was compared with data from titanium dioxide-free counterparts, Figure 1. The data for a blue hypromellose based titanium dioxide containing system chosen for comparison achieved a dE* value of less than 2 at a weight gain of 2%. The blue hypromellose based coating system with calcium carbonate did not achieve a dE* value below 2 even at the highest weight gain trialed of ~7%. The blue hypromellose based coating with calcium carbonate and isomalt achieved dE* values less than 2 at 4% or greater weight gains. Microscopy images revealed a risk of logo bridging at higher weight gains in the titanium dioxide alternative coating systems, Figure 2. Images for the blue hypromellose based coating systems with calcium carbonate revealed bridging started to appear at weight gains ~5%. In addition to bridging being observed in the calcium carbonate applied coating system, cross sectional imaging of tablet debossment showed evidence of the coating pulling away from core, Figure 3.  Imaging of the blue hypromellose based coating system with calcium carbonate and isomalt, showed clear evidence of bridging at the higher 8.8% weight gain however at the lower weight gains appeared to show potential signs of bridging in small spots in an otherwise uniform coating.

Conclusion: The results of this study showed that a titanium dioxide free color mixture system with calcium carbonate and isomalt showed potential for a replacement to titanium dioxide based on its ability to impart color uniformity at lower weight gains. The risk of bridging in the tablet debossment requires additional studies to see if the risk can be reduced to acceptable levels by evaluating the coating thermodynamic design space. The color mixtures containing calcium carbonate did not afford a pharmaceutically elegant dosage form.

References: 1 2022. 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). ed. p 1-5.

Figure 1. CIELAB color space metrics, dE*, for blue hypromellose based coating systems



Figure 3. Blue hypromellose based coating system with calcium carbonate observations of the coating pulling away from the contour of the logo.



Figure 2. Debossment bridging calcium carbonate at ~6% weight gain (left), calcium carbonate and isomalt ~9% weight gain (right)