Colouring agents or colourants or colour additives (British spelling) or Coloring agents or colorants or color additives (American spelling) are excipients used in a formulation to enhance patient compliance. From the regulatory standpoint, the term “colorant” refers to a dye or pigment used in drugs, food, or cosmetics and doesn’t migrate to them [1]. Colour is subjective, it may vary from person to person. It is a sensation that only exists inside your brain. Color of light is the combination of 7 lights that may be visible after passing a prism. Actually, all the colors are combinations of 3 main colors (red, green, and blue).
The selection of colouring agents for a pharmaceutical preparation usually coincides with or complements the flavor given to the preparation. For example, cherry-flavored pharmaceutical preparations are usually colored with red color additives, orange-flavored preparations may be colored with orange color additives and mint-flavored preparations may be colored with green or white color additives. You may also read: Emulsifying agents, Binding agents, Sweetening agents, Disintegrants used in Pharmaceuticals.
Table of Contents
Definition of Colouring Agents or Colorant or Color Additives
In pharmaceuticals, colouring agent or colorant or color additive is a pharmacologically inactive substance(s) (excipients) added to a formulation to impart color. Colorants are used in internal & external drugs as well as medical devices for producing a distinctive appearance, identification, improvement of patient compliance, protection, and printing logos and monograms. Also, color additives are used extensively in foods and cosmetics.
According to USFDA, A color additive or coloring agent is defined as any pigment, dye, or other substance that can impart color to a drug, food, or cosmetic, or to the human body [1]. In the USA, the safe and appropriate use of coloring agents is assured by the U.S. Food and Drug Administration (FDA). USFDA regulates the color Additives for Drugs, Food, Cosmetics, and Medical Devices that come in contact with the human body or animals for a significant period of time under the Federal Food, Drug, and Cosmetic Act. In addition, the European Union list coloring materials as E number such as E100 (Curcumin), E150 (Caramel).
Colorants are substances that impart color to other substances that are devoid of color (transparent, white, or gray) or modify the color of a colored substance. Moreover, some chemicals that have no color but react with another substance and produce color are called color additives. For example, dihydroxyacetone (DHA) reacts with the skin protein and imparts color.
Classification of Coloring agents or Color additives or Colorant
According to USFDA [1], Colouring agents in pharmaceuticals are classified into 3 categories:
A. Straight Colouring agents
Straight coloring agents are those coloring agents that have not been mixed or chemically reacted with any other substance. Example of straight coloring agents: FD&C Blue No. 1.
B. Lakes Colouring agents
Lakes are those coloring agents that are formed by chemically reacting straight colors with precipitants and substrata. They must be made from certified batches of straight colors except for carmine, which is a lake made from cochineal extract. Examples of lakes: Blue 1 Lake, Aluminum Lakes.
C. Mixture Colouring agents
Mixture Colouring agents are those colouring agents that have mixed one colouring agent with one or more other colouring agents or non-colored diluents, without a chemical reaction.
According to their source, colouring agents or color additives are classified as:
A. Natural colouring agents
They are produced from natural sources either vegetable or mineral sources. Natural colouring agents used in pharmaceutical preparations fall into three classes:
- Mineral-derived colouring agents: they are produced from mineral sources. For example, Red Ferric Oxide, Titanium Oxide, Lead Oxide, Copper Sulfate, and Carbon Black.
- Plant-derived colouring agents: Indigo, Beta-Carotene, Paprika, Turmeric, and Saffron.
- Animal-derived colouring agents: cochineal extract (and its lake, carmine) is derived from an insect.
B. Synthetic colouring agents
They are produced by chemical synthesizing. For example, Green S, Patent Blue V, Quinoline Yellow, Carmoisine, and Ponceau 4R.
According to solubility, Colouring agents or Colorants or Color additives are classified as:
A. Dye
Colorants that are soluble in water are called dyes. A dye is a colorant that chemically bonds to the substrate to which it is being applied. Dyes are often organic compounds. Safranin, FD&C red #4, FD&C yellow #5.
B. Pigment
Colorants that are insoluble in water are called pigments. Pigments are often inorganic compounds. For example, Red Ferric Oxide, Titanium Oxide, Lead Oxide, Indigo, Beta-Carotene, Paprika, and Copper Sulfate. Also, pigments provide useful opacity which can contribute to the stability of light-sensitive API in a dosage form such as tablets, or capsules.
C. Lakes
Lakes are largely water-insoluble forms of the common synthetic water-soluble dyes. They are prepared by adsorbing a sodium or potassium salt of a dye onto a very fine substrate of hydrated alumina, followed by treatment with a further soluble aluminum salt. The lake is then purified and dried. Lakes are frequently used in coloring tablet coatings. Examples of lakes: Blue 1 Lake, Aluminum Lakes etc.
Coloring agents approved by USFDA [1] for use with drugs are categorized into two classes:
A. Colouring agents exempt from batch certification
Colouring agents exempt from certification generally include those derived from plant or mineral sources. Such as cochineal extract (and its lake, carmine), most of the straight colors except carmine. Certification-exempt color additives must comply with the identity and purity specifications and use limitations described in their listing regulations. Users of these color additives are responsible for ensuring that the color additives comply with the listing regulations.
B. Colouring agents subject to batch certification
Color additives subject to batch certification are synthetic organic dyes, lakes, or pigments. These types of colouring agents must require certification after batch-to-batch production. For example, FD&C Blue No. 1, FD&C Blue No. 2, and D&C Blue No. 4.
List of colouring agents or colorants or color additives [1]
Colouring agents exempt from batch certification
| Name of colorants | Color | Uses |
| Alumina (dried aluminum hydroxide) | Drugs generally include eye area use. | Drugs generally. |
| Annatto extract | Orange-Red | Ingested drugs generally and external drugs including eye area use. |
| Calcium carbonate | White | Drugs generally, For surface coloring only. |
| Canthaxanthin | Reddish-Orange | Ingested drugs generally |
| Caramel | Dark-Brown | Ingested and topically applied drugs generally |
| β-Carotene | Red-Orange | Ingested drugs generally; Externally applied drugs including eye area |
| Cochineal extract | Red | Ingested and externally applied drug |
| Carmine | Deep Red | Ingested and externally applied drugs |
| Potassium sodium copper chlorophyllin (chlorophyllin-copper complex) | Green to Black | Dentifrices that are drugs (not to exceed 0.1%) |
| Dihydroxyacetone | Brown | Externally applied drugs |
| Bismuth oxychloride | White | Externally applied drugs including eye area use. |
| Synthetic iron oxide | Red, Yellow, and Black | Ingested or topically applied drugs ingested dosage by man not to exceed 5 mg/d (as Fe). |
| Ferric ammonium ferrocyanide | Blue | Externally applied drugs including eye area use. |
| Ferric ferrocyanide | Prussian Blue | Externally applied drugs including eye area use. |
| Chromium hydroxide green | Green | Externally applied drugs including eye area use. |
| Chromium oxide greens | Greens | Externally applied drugs including eye area use. |
| Guanine | Green | Externally applied drugs including eye area use. |
| Mica-based pearlescent pigments | Bluish-Gray or Grayish-White Color of Pearls | Ingested drugs not to exceed 3%. Iron not to exceed 55 wt %. |
| Pyrophyllite | Brown Green, Brownish Yellow, Greenish, Gray Green, Gray White | Externally applied drugs |
| Mica | Clear or Yellowish | Externally applied drugs including eye area use. Dentifrices. |
| Talc | Light to Dark Green, Brown, White, Grey, | Drugs generally |
| Titanium dioxide | White | Drugs generally including eye area use. |
| Aluminum powder | Silver-White | Externally applied drugs including eye area use. |
| Bronze powder | Yellow | Externally applied drugs including eye area use. |
| Copper powder | Shiny Orange-Red Metallic | Externally applied drugs including eye area use. |
| Zinc oxide | Yellow-Gray | Externally applied drugs including eye area use. |
Color additives subject to batch certification
| Name of colorants | Color | Uses and Restrictions |
| FD&C Blue No. 1 | Bright Blue | Ingested drugs generally; Externally applied drugs; Eye area use (includes lake). |
| FD&C Blue No. 2 | Indigo Blue | Ingested drugs. |
| D&C Blue No. 4 | Deep Blue | Externally applied drugs |
| FD&C Green No. 3 | Deep Green | Drugs generally |
| D&C Green No. 5 | Blackish Green | Drugs generally |
| Eye area use. | ||
| D&C Green No. 6 | Bright Green | Externally applied drugs. |
| D&C Green No. 8 | Light Green Liked Fresh Leaf | Externally applied drugs (not to exceed 0.01% (by weight)). |
| D&C Orange No. 4 | Dark Orange | Externally applied drugs |
| D&C Orange No. 5 | Orange | Externally applied drugs (not to exceed 5 mg/daily dose of drug); Mouthwashes and dentifrices. |
| D&C Orange No. 10 | Orange | Externally applied drugs |
| D&C Orange No. 11 | Orange | Externally applied drugs |
| FD&C Red No. 3 | Red | Ingested drugs. |
| FD&C Red No. 4 | Red | Externally applied drugs |
| D&C Red No. 6 | Red | Quaternary ammonium-type germicidal solutions for external application (not to exceed 0.1% (by wt) of finished drug product). |
| D&C Red No. 7 | Red | Drugs such that total with D&C Red No. 6 not to exceed 5 mg/daily dose of drug. |
| D&C Red No. 17 | Red | Externally applied drugs |
| D&C Red No. 21 | Red | Drugs generally |
| D&C Red No. 22 | Red | Drugs generally |
| D&C Red No. 27 | Red | Drugs generally |
| D&C Red No. 28 | Red | Drugs generally |
| D&C Red No. 30 | Red | Drugs generally |
| D&C Red No. 31 | Red | Externally applied drugs. |
| D&C Red No. 33 | Red | Ingested drugs, other than mouthwashes and dentifrices (not to exceed 0.75 mg/daily dose of drug); externally applied drugs; Mouthwashes and dentifrices. |
| D&C Red No. 34 | Red | Externally applied drugs |
| D&C Red No. 36 | Red | Ingested drugs, other than mouthwashes and dentifrices, not to exceed 1.7 mg/daily dose for drugs taken less than 1 yr; not to exceed 1.0 mg/daily dose for drugs taken more than 1 yr; Externally applied drugs |
| D&C Red No. 39 | Red | Quaternary ammonium type germicidal solutions for external application (not to exceed 0.1% (by wt) of finished drug product). |
| FD&C Red No. 40 | Red | Drugs generally; Eye area use (includes lake). |
| D&C Violet No. 2 | Violet | Externally applied drugs |
| FD&C Yellow No. 5 | Yellow | Ingested drugs generally; Externally applied drugs; Eye area use (includes lake). |
| FD&C Yellow No. 6 | Yellow | Drugs generally |
| D&C Yellow No. 7 | Yellow | Externally applied drugs |
| Ext. D&C Yellow No. 7 | Yellow | Externally applied drugs |
| D&C Yellow No. 8 | Yellow | Externally applied drugs |
| D&C Yellow No. 10 | Yellow | Drugs generally |
| D&C Yellow No. 11 | Yellow | Externally applied drugs |
FD&C = Food, Drug & Cosmetics, D&C = Drug & Cosmetics
Note that, the following colorants are no longer authorized for drugs:
- Bone Black
- Chlorophyll copper complex
- Charcoal NF XI
- Fustic
- Ultramarine blue – use in cosmetics is allowed
Uses of Colorants or Colouring Agents or Color additives [1, 2]
Colouring agents are a vital substance of many pharmaceutical products, making them attractive, appealing, informative, and appetizing. Color additives are used in drugs, foods, cosmetics, and medical devices. Uses of coloring agents are:
- Colouring agents are used mainly to impart a characteristic appearance to a pharmaceutical dosage form. The main categories of dosage forms that are colored are:
- Solid dosage form: Tablets: core tablet (within granules) or coated tablet (within coating materials) and Hard or soft gelatin capsules: Within capsule shell or coated beads.
- Oral liquids dosage forms such as solution, syrup, suspension, and elixir.
- Semisolid dosage forms such as creams, ointments, and pastes.
- To identify and differentiate drug products during manufacturing, packaging, distribution, and use by patients.
- The use of different colouring agents for different strengths of the same drug can also help eliminate errors.
- Coloring agents are to prevent counterfeiting.
- To improve patient acceptance because unattractive drug products can be made more acceptable to the patient.
- Coloring agents can also be used to make preparation more uniform when an ingredient in the formulation has a variable appearance from batch to batch [3].
- To provide useful opacity which can contribute to the stability of light-sensitive active materials in the formulation of tablets or capsules.
- To protect photolabile API of the dosage form.
- Colorants are used to print logos and monograms such as edible printing inks.
- Coloring agents are used in medical devices such as [Phthalocyaninato (2-)] copper in intraocular lenses, Titanium dioxide, D&C Violet #2 in Contact lenses, D&C Blue #9, Chromium-cobalt-aluminum oxide in surgical sutures. Chlorophyllin-copper complex – Polymethyl-methacrylate in Bone cement.
- Some colouring dyes are administered to a patient to get a visualization of the organ or vessels being studied. For example, methylene blue, indocyanine green, fluorescein.
Ideal properties of coloring agents or Color additives
- Nontoxic and inactive pharmacologically.
- Physically, chemically, and biologically stable.
- Free from harmful impurities.
- Must be odorless.
- Unaffected by light, tropical temperatures, hydrolysis, oxidizing or reducing agents, pH changes, and micro‐organisms.
- Stable on storage.
- Compatible with API.
- Do not interfere with the tests of preparations.
Stability of Color additives
Pharmaceutical colouring agents or Color additives have widely varying stability properties because they are chemical compounds or a mixture of chemical compounds. Inorganic pigments show excellent stability while some organic colors have poor stability properties but are used in formulations because of their low toxicity [4]. Some natural and synthetic organic colors are particularly unstable in light.
Storage Conditions of Colorants
Inorganic dyes, Lakes, and synthetic dyes should be stored in well-closed, light-resistant containers at a temperature below 30°C. Some natural colors are supplied as gelatin-encapsulated or similarly encapsulated powders and may be sealed in containers under nitrogen to extend the shelf-life.
References
- U.S. Department of Health & Human Services, U.S. Food & Drug Administration. Summary of Color Additives Listed for Use in the United States in Food, Drugs, Cosmetics, and Medical Devices. https://www.fda.gov/industry/color-additive-inventories/summary-color-additives-use-united-states-foods-drugs-cosmetics-and-medical-devices
- Rowe, Raymond C., Paul J. Sheskey, and Siân C. Owen. Handbook of Pharmaceutical Excipients. London: Pharmaceutical Press, 2006.
- Aulton ME et al. The mechanical properties of hydroxypropylmethylcellulose films derived from aqueous systems part 1: the influence of solid inclusions. Drug Dev Ind Pharm 1984; 10: 541–561.
- Delonca H et al. [Stability of principal tablet coating colors II: effect of adjuvants on color stability.] Pharm Acta Helv 1983; 58: 332–337 [in French].
Keywords: List of Colouring agents, colourants, colour additives, Coloring agents, colorants, color additives.