(T1330-03-17) Development of Hydroxypropyl Methylcellulose (HPMC)-Based, Titanium Dioxide (TiO₂)-Free Coating

Purpose: Low viscous hydroxypropyl methylcellulose (HPMC) based coating of oral solid dosage forms has been used in the pharmaceutical field for decades in order to provide desired finished form of the formulation e.g. white coating or uniform colour coating ensuring homogenous appearance between batches providing aesthetics and patience compliance. The key additive for that purpose is titanium dioxide (TiO₂), which due to its high refractive index serves as a perfect opacifier and whitening agent. The recent concerns of the European Food Safety Authority (EFSA) regarding the safety of TiO₂ as a potential genotoxic compound have led to the withdrawal of TiO₂ from its usage in the food and dietary supplement market [1]. The ban of TiO₂ has come to action in August 2022 as the EU Commission withdrew the authorization to use titanium dioxide in foods and dietary supplements (Commission Regulation (EU) 2022/63) [2]. The prohibition of the TiO₂ in the food sector shed bad light of its application in the pharmaceutical industry, although not officially banned in pharma by any authorities yet. It has been estimated that 91 000 human medicinal products and 800 veterinary medicinal products contain TiO₂ in the EU according to EU Trade Associations [3]. Any requirement to replace TiO₂ in medicines will almost certainly cause significant medicines shortages and discontinuations/withdrawals of medicines from the EU market. Here, we set out to investigate the following compounds as potential substituents to TiO₂ for a HPMC-based white coating: calcium carbonate (CaCO₃), magnesium carbonate (MgCO₃) and talc from various suppliers by film casting screening.

Methods: HPMC (5 mPas), Hypromellose 2910 (TYLOPUR® 605) was sourced from SE Tylose GmbH & Co. KG (Wiesbaden, Germany). TiO₂ was received from Kronos (Germany). Ten grades of calcium carbonate (CaCO₃) were sources from five different suppliers: Elite 150, 250, 500, 850, 950 from Huber (USA); Calopake® Extra Light from Minerals Technologies (UK); Scoralite® from Scora (Italy), Magnesia 4421, Magnesia 4461 from Magnesia (Germany) and Calcipur 110-KP from Omya (Switzerland). Magnesium carbonate (MgCO₃) was provided by Scora (Italy). Talc was obtained from Nippon Talc (Japan). Suspension for film casting was prepared by mixing: TYLOPUR® 605 (15%,w/w) and one of the tested additives: TiO₂, CaCO₃, MgCO₃, or Talc with the amount of 15% (ratio on polymer) in hot water while steering (2 h cooling at room temperature). Films were prepared by casting at 1000um thickness on a glass plate. Films were dried in the room temperature for at least 24 hours (final film thickness - around 100um). The opacity of the films was measured by X-Rite (X-Rite Incorporated, USA).

Results: In this study we investigated the opacity of the tested potential substituents of TiO₂: CaCO₃, MgCO₃ and Talc by casing the HPMC-based film and measuring achieved opacity. We sourced the ingredients from various manufacturers aiming to have a broad representation of the tested compounds in terms of their physico-chemical properties e.g. ten grades of CaCO₃ from five producers, among which five grades of CaCO₃ originate from one source and vary in the particle size (Huber). The opacity measurement of the cast films showed that the sourcing of CaCO₃ is a crucial step to reach the highest possible opacity before the film coating trials. We obtained the span of 24% difference in opacity between the tested grades of CaCO₃ scoring the highest number of 45% with Calopake® Extra Light and as low as 21% with Scoralite® (Figure 1). Interestingly, among the 5 grades of CaCO₃ provided by one manufacturer with the varying particle size we observed a dependency between the opacity and particle size – the highest opacity was reached using the material of the smallest particle size (Huber); The highest value of opacity was obtained from MgCO₃ – 47% (Figure 1). Nevertheless, none of the ingredients tested could reach the opacity close to the one provided by TiO₂ – 90% (Figure 1).

Conclusion: Currently the feasibility of replacing TiO₂ in pharmaceuticals is assessed by European Medices Agency (EMA), which triggers a massive motion among pharmaceutical companies to seek for a TiO₂ replacement. We have tested here 10 grades of the most popular substituent of TiO₂ namely CaCO₃, MgCO₃, and Talc testing their opacity capacity dependent of physico-chemical properties of material sourced from different manufacturers using HMPC-based cast films. We have shown that it is important to evaluate different sourcing of minerals for the further trials since the origin, ways of manufacturing as well as material properties can greatly influence final results – opacity difference of 24% between the best and worst performing CaCO₃ grade. We have shown that the particle size of CaCO₃ plays a crucial role in opacifying performance of the material. We have concluded that none of the single compounds used in the screening is compatible with the performance of TiO₂, the best performing CaCO₃ provided only around half of the opacity of the one provided by TiO₂.

References: 1. Safety assessment of titanium dioxide (E 171) as a food additive, adopted 25 March 2021; EFSA Journal Volume 19 (May 2021).
2. Commission Regulation (EU) 2022/63 of 14 Jan 2022; Official Journal of the European Union L 11/1 (18 January 2022).
3. Final feedback from European Medicine Agency (EMA) to the EU Commission request to evaluate the impact of the removal of titanium dioxide from the list of authorised food additives on medicinal products EMA/504010/2021.

Figure1. Opacity of HPMC-based cast films using TiO2, CaCO3, MgCO3 and Talc as additives.