Colouring agents in pharmaceuticals

Colouring agents (British spelling) or Coloring agents (American spelling) also known as Color Additives, Colorant. From the regulatory standpoint, the term “colorant” refers to a dye or pigment used in drugs, food, or cosmetic and doesn’t migrate to them [1]. Colour is subjective, it may vary from person to person. Colour is a sensation that only exists inside your brain. Color of light is the combination of 7 lights that may visible after passing a prism.  Actually, all the colors are combinations of 3 main colors (red, green, and blue).

In pharmaceuticals, the selection of a colouring agent 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. 

Definition of Colouring Agents or Color Additives

In pharmaceuticals, colouring agent or color additive is a pharmacologically inactive substance(s) (excipients) added to a formulation to impart color. Color additives are used in internal & external drugs as well as medical devices for producing a distinctive appearance, identification, improvement of patient compliance, protection, and printing logo and monogram. 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).

Color additives 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 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 colouring agents are those colouring agents that have not been mixed or chemically reacted with any other substance. Example of straight colouring agents: FD&C Blue No. 1.

B. Lakes Colouring agents

Lakes are those colouring agents that are formed by chemically reacting straight colors with precipitants and substrata. They must be made from certified batches of straight colors except 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 from 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 color additives are classified as: 

A. Dye

Colouring agents which are soluble in water are called dye. A dye is a colouring agent 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

Colouring agents which are insoluble in water are called pigment. 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, 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.

Colouring 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.

Coloring agents used in pharmaceuticals

List of colouring agents or color additives [1]

Colouring agents exempt from batch certification

Name of Color additivesColorUses
Alumina (dried aluminum hydroxide)WhiteDrugs generally.
Annatto extractOrange-RedIngested drugs generally and external drugs including eye area use.
Calcium carbonateWhiteDrugs generally, For surface coloring only.
CanthaxanthinReddish-OrangeIngested drugs generally
CaramelDark-BrownIngested and topically applied drugs generally
β-CaroteneRed-OrangeIngested drugs generally; Externally applied drugs including eye area
Cochineal extractRedIngested and externally applied drug
CarmineDeep RedIngested and externally applied drugs
Potassium sodium copper chlorophyllin (chlorophyllin-copper complex)Green to BlackDentifrices that are drugs (not to exceed 0.1%)
DihydroxyacetoneBrownExternally applied drugs
Bismuth oxychlorideWhiteExternally applied drugs including eye area use.
Synthetic iron oxideRed, Yellow, and BlackIngested or topically applied drugs ingested dosage by man not to exceed 5 mg/d (as Fe).
Ferric ammonium ferrocyanideBlueExternally applied drugs including eye area use.
Ferric ferrocyanidePrussian BlueExternally applied drugs including eye area use.
Chromium hydroxide greenGreenExternally applied drugs including eye area use.
Chromium oxide greensGreensExternally applied drugs including eye area use.
GuanineGreenExternally applied drugs including eye area use.
Mica-based pearlescent pigmentsBluish-Gray or Grayish-White Color of PearlsIngested drugs not to exceed 3%. Iron not to exceed 55 wt %.
PyrophylliteBrown Green, Brownish Yellow, Greenish, Gray Green, Gray WhiteExternally applied drugs
MicaClear or YellowishExternally applied drugs including eye area use. Dentifrices.
TalcLight to Dark Green, Brown, White, Grey,Drugs generally
Titanium dioxideWhiteDrugs generally including eye area use.
Aluminum powderSilver-WhiteExternally applied drugs including eye area use.
Bronze powderYellowExternally applied drugs including eye area use.
Copper powderShiny Orange-Red MetallicExternally applied drugs including eye area use.
Zinc oxideYellow-GrayExternally applied drugs including eye area use.

Color additives subject to batch certification

Name of Color additivesColorUses and Restrictions
FD&C Blue No. 1Bright BlueIngested drugs generally; Externally applied drugs; Eye area use (includes lake).
FD&C Blue No. 2Indigo BlueIngested drugs.
D&C Blue No. 4Deep BlueExternally applied drugs
FD&C Green No. 3Deep GreenDrugs generally
D&C Green No. 5Blackish GreenDrugs generally
Eye area use.
D&C Green No. 6Bright GreenExternally applied drugs.
D&C Green No. 8Light Green Liked Fresh LeafExternally applied drugs (not to exceed 0.01% (by weight)).
D&C Orange No. 4Dark OrangeExternally applied drugs
D&C Orange No. 5OrangeExternally applied drugs (not to exceed 5 mg/daily dose of drug); Mouthwashes and dentifrices.
D&C Orange No. 10OrangeExternally applied drugs
D&C Orange No. 11OrangeExternally applied drugs
FD&C Red No. 3RedIngested drugs.
FD&C Red No. 4RedExternally applied drugs
D&C Red No. 6RedDrugs such that total with D&C Red No. 7 not to exceed 5 mg/daily dose of drug.
D&C Red No. 7RedDrugs such that total with D&C Red No. 6 not to exceed 5 mg/daily dose of drug.
D&C Red No. 17RedExternally applied drugs
D&C Red No. 21RedDrugs generally
D&C Red No. 22RedDrugs generally
D&C Red No. 27RedDrugs generally
D&C Red No. 28RedDrugs generally
D&C Red No. 30RedDrugs generally
D&C Red No. 31RedExternally applied drugs.
D&C Red No. 33RedIngested 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. 34RedExternally applied drugs
D&C Red No. 36RedIngested 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. 39RedQuaternary ammonium type germicidal solutions for external application (not to exceed 0.1% (by wt) of finished drug product).
FD&C Red No. 40RedDrugs generally; Eye area use (includes lake).
D&C Violet No. 2VioletExternally applied drugs
FD&C Yellow No. 5YellowIngested drugs generally; Externally applied drugs; Eye area use (includes lake).
FD&C Yellow No. 6YellowDrugs generally
D&C Yellow No. 7YellowExternally applied drugs
Ext. D&C Yellow No. 7YellowExternally applied drugs
D&C Yellow No. 8YellowExternally applied drugs
D&C Yellow No. 10YellowDrugs generally
D&C Yellow No. 11YellowExternally applied drugs

FD&C = Food, Drug & Cosmetics, D&C = Drug & Cosmetics

Note that, the following color additives is no longer authorized for drugs:

  • Bone Black
  • Chlorophyll copper complex
  • Charcoal NF XI
  • Fustic
  • Ultramarine blue – use in cosmetics is allowed

Uses of 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 colouring agents are:

  1. Colouring agents are used mainly to impart a characteristic appearance to a pharmaceutical dosage form. The main categories of dosage form 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 form such as solution, syrup, suspension, elixir.
  • Semisolid dosage forms such as creams, ointments, and pastes.
  1. To identify and differentiate drug products during manufacturing, packaging, distribution, and using by patients.
  2. The use of different colouring agents for different strengths of the same drug can also help eliminate errors.
  3. Coloring agents are to prevent counterfeiting.
  4. To improve patient acceptance because unattractive drug products can be made more acceptable to the patient.
  5. Coloring agents can also be used to make preparation more uniform when an ingredient in the formulation has itself a variable appearance from batch to batch [3].
  6. To provide useful opacity which can contribute to the stability of light-sensitive active materials in the formulation of tablet or capsule.
  7. To protect photolabile API of the dosage form.
  8. Coloring agents are used to print logo and monogram such as edible printing inks.
  9. 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.
  10. 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

  1. Nontoxic and inactive pharmacologically.
  2. Physically, chemically, and biologically stable.
  3. Free from harmful impurities.
  4. Must be odorless.
  5. Unaffected by light, tropical temperatures, hydrolysis, oxidizing or reducing agents, pH changes, and micro‐organisms.
  6. Stable on storage.
  7. Compatible with API.
  8. 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 colorant 

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

  1. 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
  2. Rowe, Raymond C., Paul J. Sheskey, and Siân C. Owen. Handbook of Pharmaceutical Excipients. London: Pharmaceutical Press, 2006.
  3. 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.
  4. 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].