Stability impact from a titanium dioxide-free film-coated tablet: An analytical investigation into photo-, physical, and chemical stability of compressed tablets made with alternative film-coating materials

Titanium Dioxide (E171 Grade, TiO₂) is a commonly used excipient within food and pharmaceutical products, widely utilized for its unique properties as an opacifier and colorant while being non-toxic and inert.1, 2, 3 A survey conducted in 2021 by the European Medicines Agenda (EMA) estimated that nearly 70 % of all tablets manufactured by the surveyed companies contained TiO₂. While considered safe for consumption and used for over fifty years in pharmaceutical products, recent studies have raised concerns over the impact of long-term exposure to nano-sized TiO_2. In 2022, the EMA began banning TiO₂ for use within food products due to its suspected carcinogenic properties and recent legislative proposals within the United States shows many states have efforts to pass similar restrictions. While these findings have been challenged by the FDA and experts in the field⁸, this has nevertheless led to the rapid evaluation of potential replacements with the ideal material possessing comparable attributes as an opacifier and colorant to TiO₂.

Replacements for TiO₂ within drug products has been sparsely studied until recently. A review of these studies published in 2022 by the IQ Consortium Working Group has indicated that minimal success has been found in TiO₂ alternatives due to replacements being inferior opacifiers, difficulties creating a uniform tablet appearance, and observations of color fading. Only two published assessments were identified by the IQ Consortium Review with neither concluding that a direct replacement for TiO₂ could be found and that replacement coating would have to be evaluated on a case-by-case basis. In addition, alternative film coats are expected to have in vitro and in vivo impacts as well. Further, it is expected that any replacement would require a higher weight gain of film coating due to opacity concerns compared to TiO₂. Additional studies have since been reported as the pharmaceutical industry continually evaluates replacements, including case studies evaluating alternative film coats impact on light protection, film coat adhesion, appearance, and dissolution.13, 14, 15 Throughout all of these studies, no fully equivalent replacement for TiO₂ with all of the requisite characteristics as an opacifier or colorant has been identified.

Herein, replacement efforts of TiO₂ within the film-coated tablet (FCT) of a product under development at Merck & Co., Inc., Rahway, NJ, are discussed. Replacement efforts for this product contained a unique set of challenges as the final fixed-dose combination product contains two co-formulated active pharmaceutical ingredients, API A and API B, each of which has known degradation pathways (Scheme 1). API A is a BCS Class I compound and a base-labile API. API B is a BCS Class II compound and has internally been shown to degrade under UV light, forming a phenol-related degradant and undergoing a color change from white to blue due to a second degradant theorized to be a dimerized bi-product of the photodegradants. In addition, API B is produced as a spray-dried intermediate (SDI), known to crystallize at elevated temperature and relative humidity conditions, which can potentially change physical form under the longer film coat processing time needed for TiO₂ replacements. Two leading TiO₂ replacement options being closely examined by the experts are calcium carbonate (CaCO₃), a known base, and rice starch from natural products. A thorough investigation into the photostability, physical stability, and chemical stability of the fixed-dose combination drug product was designed and implemented to assess the feasibility of replacing TiO₂ with three potential candidates detailed in Table 1: a CaCO₃-based coating (Film Coat B), two rice starch-based coatings (Film Coat C and Film Coat D), and a control film coat containing no opacifiers (Film Coat E). Tablets containing a TiO₂-based coating (Film Coat A) were carried through adjacent studies for use as a control and were used to demonstrate the comparability of replacement coatings. Photo-, chemical, and physical- stability were assessed using chromatography, spectrometry, physical measurements, and colorimetry and will be compared to existing TiO₂-coated tablets.