Titanium dioxide, that is, let's start from the beginning.

Titanium dioxide (TiO)₂) is an odorless white-gray solid. Colloquially, it is referred to as “titanium white” (in the manufacture of dyes) or “titanium”. In the natural environment, it is found in three crystalline forms: rutile, anatase, brucite.
History of TiO₂ It began in 1791 in Cornwall and was discovered by William Gregor. However, it was not until 1916 that this compound began to be produced on a commercial scale. Titanium dioxide has found wide application in many industries (Figure 1).

The end of the era of titanium dioxide.

So far, titanium dioxide has been treated as a food additive¹ and was subject to Regulation (EC) No 1333/2008 of the European Parliament and of the Council of 16 December 2008 on food additives, in which, in Part B of Annex II, it was assigned the number E 171, performing the function of a dye.

     On 14.01.2022, the European Commission introduced a ban on the use of TiO by Regulation 2022/63₂ in food (the temporary ban does not cover medicinal products in accordance with Directive 2009/35/W of the European Parliament and of the Council). The reason for the changes was to question the safety of the consumption of E 171 as a food additive, due to its potential genotoxicity.
The assessment of the overall benefit/risk profile of abrupt discontinuation of titanium dioxide in medicinal products showed that this would have a negative impact on the quality, safety and efficacy of medicinal products. The time it takes to reformulate an individual product can take several years - this would lead to significant shortages of medicines on the EU market. Dietary supplements in the European Union are legally regulated as food and as defined by EFSA (European Food Safety Authority) are a concentrated source of vitamins and minerals or other substances with nutritional or physiological effects, therefore they should be safe in the first place. Therefore, for this group, the transition period for the removal of TiO₂ from the composition of products amounted to only 6 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 different dose levels of the products from each other. The dye primarily protects the contents of the inside of the tablets or capsules from direct sunlight, 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 Regulation No 1333/2008 of the European Parliament and of the Council, each of which is assigned an E number. Four groups of dyes can be distinguished (Figure 2), each of them will have different properties and not each of them will work for each form and technology of the supplement. Natural dyes can degrade over time, losing their color or even changing it, for example by darkening.
Withdrawal from use of commonly known and used TiO dye₂ proved to be a challenge for producers of both raw materials and finished products using E 171 to date. Due to its neutral taste and odour, chemical inertness, opacity, excellent coverage with deep white, and at the same time high protection against UV light, titanium dioxide has been a popular ingredient in hard capsule shells, soft capsules, and Tablets as well. It has not only been used for obtaining a snow-white color, but also for increase in intensity and opacity others colors areola. Decrease in light transmittance through the coating layer makes it possible to avoid negative effects on the contents of capsules or tablets, this prevents negative processes so that the finished product can be stored longer and stable.
It is not easy to find a suitable replacement for E 171 while retaining all its functionalities from the dyes currently in force, usually manufacturers try to achieve the desired effect by using other permitted additives in different combinations, depending on the target product. These include, among others, calcium carbonate, rice starch, corn starch, or sodium salt of starch octenyl succinate.

Difficulty — the process of coating tablets.

An additional aspect in the process of coating the tablet cores is the value of the increment of the shell for which the tablet will be completely coated. Using TiO₂ we were able to achieve the desired effect already with ~ 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. However, by coating the same type of cores with a titanium dioxide-free shell, we are able to obtain a satisfactory result with up to twice the amount of coating agent. The process takes a lot longer, which generates raw material, energy and production costs. It is easier to achieve the effect of spots and uneven color, so it is very important that the operator remains vigilant during the process to avoid poor product quality. It is worth noting that no amount of shell without TiO2 will have such a deep and uniform color as the one containing it, nor will the white be snow-white.
As the Europharma Alliance, we have already had several changes to the formulation of tablet coating envelopes. Together with long-standing suppliers, we tested various replacement proposals even before the European Commission banned the use of E 171 in food. In Fig. 3 the effects of several of them.

Trouble — hard capsule shells.

     In the market of hard capsule shells, we can distinguish, due to the type of main ingredient, the two most popular groups: gelatin and HPMC (hydroxypropyl methylcellulose). Each of them has different properties, behaves differently on the machine and interacts with the components of the filling. Regardless of the main material, these tinted TiO₂ were white and opaque, even despite the dark filling. At the moment, no replacement E 171 will have the same properties as the original, as shown in Figure 4. By removing the titanium dioxide from the composition, we lose opacity and dark fillings can be distinguished.
Manufacturers of hard capsule shells assure that calcium carbonate (CaCO₃) is the closest alternative to the previous white dye. It retains functional properties, including protection from light, despite being semi-transparent. It is worth mentioning that CaCO₃ is mainly recommended for HPMC envelopes, in the case of gelatin envelopes, damage and breakage of capsules may occur. In different ways, manufacturers of gelatin envelopes try to color them, so as not to lose their properties and meet all requirements. Mostly these are their own, individual recipes of each.
In order to fully protect the supplement in the form of hard capsules (especially sensitive to the external environment components, such as vitamin K), we often recommend to our Clients opaque unit packages, i.e. opaque jars or white PVC/PVDC blister films.

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‍What about soft capsules?

When it comes to soft capsules, we are the manufacturer of envelopes for ourselves. The gelatin mass before the liquid encapsulation stage should be definitely fresh, with the right temperature and produced on site, so as manufacturers of soft capsules we have influence on what dye we use in the composition. We do not produce TiO coloured soft capsules₂, because when putting into operation the new encapsulation line we have already taken into account the upcoming withdrawal of titanium dioxide from use. From the same group of suspension dyes to which titanium dioxide belonged - fully covering - we are happy to use iron oxides (red, black, brown or yellow), but at the request of customers we can also use other dyes.

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Time of Summaries

Considered until now, the ideal and universal ingredient in capsule and tablet shells — titanium dioxide (E 171) — has been banned for use in the European Union. Despite the difficulty of finding an analogous alternative, we are able to find a suitable replacement for it. The main distinguishing feature of the search is the form of the preparation for which we are looking for an alternative TiO₂. Depending on whether it will be tablets, hard capsules OR soft, the solution will be ambiguous. An additional way to protect the contents of the product can also be to change the type of unit packaging. Nevertheless, consumers must take into account the fact that the product they buy so far can change not only visually, but above all in terms of composition - the purpose of these changes is the safety of the finished product.

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¹“FOOD ADDITIVE” means any substance which, under normal conditions, is neither consumed by itself as a food nor used as a characteristic food ingredient, whatever its nutritional value, the intentional addition of which, for technological reasons, to food during its manufacture, processing, preparation, treatment, packaging, transport or storage causes, or can reasonably be expected to cause, that substance or its derived products become, directly or indirectly, an ingredient in that food.'. [Regulation No 1333/2008]