Titanium dioxide, let's start from the very beginning.

Titanium dioxide (TiO₂) is an odorless white-gray solid. It is commonly referred to as "titanium white" (in dye production) or "titanium". In the environment it occurs in three crystalline forms: rutile, anatase, brucite. The history of TiO₂  began in 1791 in Cornwall when it was discovered by William Gregor. However, it was not until 1916 that the compound began to be produced on a commercial scale. Titanium dioxide has been widely applied in many industries (Figure 1).

The end of the titanium dioxide era.

     Until recently, titanium dioxide was treated as a food additive¹  and fell under Regulation (EC)No. 1333/2008 of the European Parliament and of the Council of December 16,2008 on food additives, in which number E171 it was assigned to it in Annex II, Part B, and the function of a colorant.

    The European Commission banned the use of TiO₂  in food as of 14.01.2022 by Regulation 2022/63 (the ban temporarily excludes medicinal products in accordance with Directive 2009/35/W of the European Parliament and of the Council). The reason for the change was to doubted safety of consuming E 171 as a food additive due to its potential genotoxicity.
     An assessment of the overall benefit-risk profile of abruptly discontinuing titanium dioxide in medicines showed that this would have a negative impact on the quality, safety and efficacy of medicinal products. The time required to reformulate an individual product could take several years - this would result in significant drug shortages on the EU market. Dietary supplements in the European Union are regulated by law as food, and according to the EFSA (European Food Safety Authority)
definition they are a concentrated source of vitamins and minerals or other substances with nutritional or physiological effects, and should therefore be primarily safe. Therefore, for this group, the transition period for removing TiO₂ from product formulations was only six months.

How to produce now?

    The color of the preparations, is not only a visual aspect and attractiveness, but is also an important issue so that the consumer can distinguish between different levels of product dosage. Above all, the colorant protects the contents inside the tablets or capsules from direct sunlight by taking care of the stability of the active ingredients.

The type and amount of dye that can be used in the European Union is determined by the Regulation of the European Parliament and of the Council No. 1333/2008, each of which is assigned its own E number. Four groups of dyes can be distinguished (Fig. 2), each of which will have different properties and not all of them will work for every form and technology of the supplement. Natural dyes can degrade overtime, losing their color or even changing it, for example by darkening.      
The phase out of the well-known and widely used TiO₂ proved to be a challenge for manufacturers of both raw materials and finished products using E 171. Due to its neutrality of taste and odor, chemical inertness, opacity, excellent deep white coverage, and high protection against UV light, titanium dioxide was a popular ingredient in the shells of hard and soft capsules, as well as tablets. It was used not only for obtaining snow-white color, but also for increasing the intensity and opacity of other colors. Reducing the light transmission through the coating layer makes it possible to avoid negative effects on the contents of capsules or tablets, it prevents negative processes so that the finished product can be stored safely for a longer period of time.
     It is not easy to find a suitable substitute for E 171 while retaining all its functionality from available colorants. Usually manufacturers try to achieve the desired effect by using other permitted additives in various combinations, depending on the target product. These include calcium
carbonate, rice starch, corn starch, or starch octenyl succinate sodium.

Difficulty - the process of coating tablets.

     An additional consideration when coating tablet cores is the value of the shell gain till it is completely coated. Using TiO₂  we were able to achieve the desired effect with as little as ~2% weight gain, depending on the type of core and the size of the tablet. As mentioned, titanium dioxide is highly opaque, so the process was relatively short and efficient. In contrast, by coating the same type of cores with a titanium dioxide-free coating, we are able to achieve a satisfactory result with up to twice the amount of coating agent. The process thus takes much longer, which generates raw material, energy and production costs. It is also easier to get a speckled effect and uneven coloration, so it is highly important for the operator to be vigilant when conducting the process to avoid obtaining a poor quality product. It is worth noting that no shell without TiO2 will be as deep and uniform in color as one containing it, nor will the white be snow white.      
As Europharma Alliance, we have already had several formulations changes of tablet coating. Together with our trusted suppliers, we tested various replacement proposals even before the European Commission banned the use of E171 in food. Figure 3 shows the effects of several of them.

‍

Trouble - hard capsule shells.

Hard capsule shells market, can be divided based on the type of the main ingredient. The most popular groups are: gelatin and HPMC (hydroxypropyl methyl cellulose). Each of them has different properties, behaves differently on the machine and interacts with the filling components. Regardless of the main material, these TiO-dyed₂ were white and opaque, covering even dark filling. At this point, no substitute for E 171 will give back the same properties as the original, this is shown in Figure 4. By getting rid of the titanium dioxide from the formulation, the opacity is lost and dark fillings can stand out.
   Manufacturers of hard capsule shells assure that calcium carbonate (CaCO₃) is the closest alternative to the previous white dye. It retains functional properties including light protection, despite its translucency. It is worth mentioning that CaCO₃ is mainly recommended for HPMC shells, for gelatin shells it can lead to breaking and chipping of the capsules. In various ways, manufacturers of gelatin shells try to color them, not lose their properties and to meet all requirements. Each manufacturer tries to come up with their own individual formulations.
    In order to fully protect the supplement in the form of hard capsules (especially the ones sensitive to the external environment, such as vitamin K), we often recommend opaque unit packaging to our customers, i.e. opaque jars or white PVC/PVDC blister films.

What about soft capsules?

 When it comes to soft capsules, we are the manufacturer of the shells for ourselves. The gelatin mass before the liquid encapsulation stage should definitely be fresh, at the right temperature and produced in-house, so as soft capsule manufacturers, we have a say what dye to use in the formulation. We have never produced soft capsules dyed with TiO₂, as we were already taking into account the upcoming phase-out of titanium dioxide when we launched our new capsule line. From the same group of suspension dyes to which titanium dioxide belonged to - fully opaque - we are happy to use iron oxides (red, black, brown or yellow), but we can also use other dyes on request.

Summary

     Considered, until recently, to be the ideal and universal ingredient for capsule and tablet shells - titanium dioxide (E 171) - has been banned for use in the European Union. Despite the difficulty of finding an alternative, we are able to find a suitable substitute for it. The primary distinguishing feature of the search for a TiO₂-free alternative is the form of the preparation. Depending on whether it is tablets, hard capsules or soft capsules, the solution will still be ambiguous. An additional way to protect the contents of the product may also be to needed – for example a change of primary packaging. Nevertheless, consumers must expect that the product they used to buy may and most probably will change not only visually, but especially in terms of composition - the purpose of these changes is the safety of the finished product.

‍

¹"FOOD ADDENDUM shall mean any substance that is normally neither consumed alone as food nor used as a characteristic ingredient of food, regardless of its possible nutritional value, the intentional addition of which, for technological reasons, to food in the course of its production, processing, preparation, treatment, packaging, transportation or storage causes, or may reasonably be expected to cause, the substance or its derivatives to become directly or indirectly an ingredient of that food." [Regulation No. 1333/2008].