Benjamin Stephan, technical project and marketing manager at BIOGRUND US Inc.
Ask an Expert – TiO2 replacement in tablet film coating
Q: What are the natural white pigments that can replace titanium dioxide, and how easy is it to reformulate an existing film coating?
A: Benjamin Stephan, Biogrund US, say:
Titanium dioxide (TiO2), commonly referred to as E171, is widely used as a whitening agent and is one of the most important food additives in nutraceuticals. Consumer concerns about TiO2 stem from several disputed studies that described a potential risk to the human respiratory system from TiO2 nanoparticles [1]. Potential risks exist because TiO2 nanoparticles may accumulate after inhalation or oral exposure in the lungs, alimentary tract, liver, heart, spleen, kidneys, and cardiac muscle.
Whether these concerns are warranted or not is unclear. The European Commission regularly evaluates the safety of food additives. In response to an evaluation of TiO2 in April 2019 by the French Agency for Food, Environmental, and Occupational Health and Safety (ANSES), the commission requested that the European Food Safety Authority (EFSA) provide urgent scientific and technical assistance regarding the opinion [2]. ANSES had examined recent scientific studies on the additive and found that none of them was robust enough to confirm or rule out potential harmful effects. EFSA agreed that uncertainties and data gaps still exist.
The demand for nutraceutical products that are free of TiO2 is also part of a consumer-driven trend called the Clean Label movement. A Clean Label product must use familiar, simple ingredients that are easy to recognize, understand, and pronounce.
TiO2 doesn’t stand alone in this trend. Consumers have driven the movement to replace all artificial ingredients in nutraceuticals with natural ingredients, to require nutritional information about ingredients on labels, and to require transparency in ingredient labels.
Demand for TiO2-free OTC and other pharmaceutical products is also slowly beginning to grow. Some regulatory bodies have supported this movement, and France has even banned the use of TiO2 in food.
As a result, the nutraceutical and pharmaceutical industries are looking for alternatives to critical solid dosage excipients, including flow agents, lubricants, binders, fillers, and pigments. In addition to TiO2, manufacturers are currently evaluating alternatives to synthetic colors, iron oxides, silicon dioxides, magnesium stearates, and talc.
This demand for new, consumer-friendly ingredients is creating challenges for brand owners and contract manufacturing organizations (CMOs), which must:
- Find natural ingredients that are not genetically modified;
- Source organic ingredients where available;
- Keep products allergen and gluten-free;
- Minimize the use of additives and fillers; and
- Make formulation adjustments in response to changes in regulatory requirements.
Formulation challenges
Developing TiO2-free film-coating formulations is challenging because TiO2 has a higher refractive index and brightness than other white pigments, so even a small amount can significantly influence a product’s appearance. This means that alternative pigments must be present in larger amounts than TiO2 to obtain the same whitening effect. However, required amounts of functional excipients limit the amount of pigment a coating formulation can contain.
Developing an alternative coating formulation that provides comparable functionality, brightness, and opacity and that uses preparation and application methods like those used for TiO2-based coating formulations, can be difficult. Possible natural replacements for TiO2 include carbonates, phosphates, and starches.
Case study
BIOGRUND conducted the following case study to investigate possible substitutes for TiO2. Therefore, 12 formulations using five replacement pigments at a range of different particle sizes were developed. The core formulation comprised various vitamins that are widely used in nutraceuticals. The trials were performed in a standardized film-coating process in a fully perforated drum coater as well as a comparison of tablet weight-gain levels.
The investigated film-coating properties were opacity, brightness, film flexibility, film strength, film surface, and viscosity. Compared to a reference tablet (Figure 1), the best TiO2-free formulation achieved a standard deviation of 1.2 Delta E (ΔE),which is the standard calculation metric that describes the capacity of the human eye to perceive differences between two colors. A colorimeter, a color measuring instrument, can provide this metric. In Figure 1, the colors used in the cells represent a traffic light system that evaluates the results: green = good or very good; yellow = acceptable; and red = out of specification or not acceptable. Figure 1 shows a green result for all properties except for brightness, for which yellow was the best result that the study could achieve.
A 1:1 exchange wasn’t possible. The results of all coating trials showed that only a mixture of several substances could replace TiO2 in the coating formulation. Additionally, a higher weight gain was necessary to achieve the required coating properties using the replacement formulation.
The study found that suitable clean-label replacements for TiO2 in film coatings are available. A mixture of several raw materials can provide a TiO2-free film coating with properties that are comparable to a TiO2-based coating.
Reformulation
The reformulation of existing nutraceutical TiO2 formulas to TiO2-free formulas requires that you examine each formulation individually. Since the various dietary ingredients in a raw tablet core often differ in color, you must develop a customized film-coating formulation to achieve the white tablet surface that consumers expect (photo).
Professional laboratory equipment can help in determining an alternative pigment’s visible brilliance and lightness. Using a spectrophotometer, you can measure the color space of a tablet surface with the CIELab method, a color space that the International Commission on Illumination has specified [3]. The method expresses color as three values: 1) L—the lightness, running from black (0) to white (100); 2) a—running from green (-) to red (+); and 3) b—running from blue (-) to yellow (+). L100 is the highest achievable value. For the TiO2-free film-coating reformulation in the case study, the value was L95, while the value for the TiO2 reference film coating was L97 and the value for the uncoated, brown placebo tablet was L65.
The easiest way to avoid TiO2 is to choose a clear coating formulation, but your marketing department will need to decide if that’s the most suitable approach for the product, since color is important for branding as well for identification.
For pharmaceutical products, applying a TiO2-free coating will be easier because most tablet cores are naturally white. With alternative formulations for a titanium dioxide replacement a comparable opacity to that of TiO2-coated tablets can be achieved.
References
- Original article published on April 20 in “Tablets & Capsules”
- Springer open access. Effects of Titanium Dioxide Nanoparticles Exposure on Human Health—A review, April 2019.
- European Food Safety Authority (EFSA). EFSA statement on the review of the risks related to the exposure to the food additive titanium dioxide (E 171) performed by the French Agency for Food,Environmental and Occupational Health and Safety (ANSES). June 12, 2019.
- Datacolor. Colorimetric Fundamentals,2009