Name: Coloring Agents
CAS No: See Tables I, II, III, and IV
See Section 17 and Tables I, II, III, and IV
See Section 17 for specific, selected coloring agents
See Tables I, II, III, and IV
See Section 17 for specific selected coloring agents
See Section 17 for specific selected coloring agents
Coloring agents are used mainly to impart a distinctive appearance to a pharmaceutical dosage form. The main categories of dosage form that are colored are: . Tablets: either the core itself or the coating. . Hard or soft gelatin capsules: the capsule shell or coated beads. . Oral liquids. . Topical creams and ointments. Color is a useful tool to help identify a product in its manufacturing and distribution stages. Patients, especially those using multiple products, often rely on color to be able to recognize the prescribed medication.(1) The use of different colors for different strengths of the same drug can also help eliminate errors. Many drug products look similar; hence color in combination with shape and/or an embossed or printed logo can help with identification. Also, this combination can assist in the prevention of counterfeiting. Unattractive medication can be made more acceptable to the patient by the use of color, and color can also be used to make a preparation more uniform when an ingredient in the formulation has itself a variable appearance from batch to batch.(2) Some of the insoluble colors or pigments have the additional benefit when used in tablet coatings or gelatin shells of providing useful opacity, which can contribute to the stability of light-sensitive active materials in the tablet or capsule formulation. Pigments such as the iron oxides, titanium dioxide, and some of the aluminum lakes are especially useful for this purpose.(3) Of the many classifications possible for pharmaceutical coloring agents, one of the most useful is to simply divide the colors into those that are soluble in water (dyes) and those that are insoluble in water (pigments). Colors for clear liquid preparations are limited to the dyes;(4) e.g. see Section 17. For surface coloration, which includes coated tablets, the choice of color is usually restricted to insoluble pigments. The reasons for this include their lack of color migration, greater opacity, and enhanced color stability over water-soluble colors.(5) 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.(6) Lakes are frequently used in coloring tablet coatings since, for this purpose, they have the general advantages of pigments over water-soluble colors.
The physical appearances of coloring agents vary widely. See Section 17 for specific selected coloring agents.
Some materials used as pharmaceutical coloring agents are included in various pharmacopeias; for example, titanium dioxide is included in the PhEur 6.4. However, if titanium dioxide is being used exclusively as a colorant, then the specific purity criteria from Directive 95/45/EC apply.(7)
Typical properties of specific selected coloring agents are shown in Section 17. Selected properties are shown in Tables V, VI, and VII
Pharmaceutical coloring agents form a chemically diverse group of materials that have widely varying stability properties. Specific information for selected colors is shown in Table VII and can be found in Woznicki and Schoneker.(4) See also Section 17. While some colors, notably the inorganic pigments, show excellent stability, other coloring agents, such as some organic colors, have poor stability properties but are used in formulations because of their low toxicity.(8) Some natural and synthetic organic colors are particularly unstable in light. However, with appropriate manufacturing procedures, combined with effective product packaging, these colors may be used successfully in formulations, thus making a wide choice of colors practically available. Lakes, inorganic dyes, and synthetic dyes should be stored in well-closed, light-resistant containers at a temperature below 308C. For most natural and nature-identical colors, the storage conditions are more stringent and a manufacturer’s recommendations for a particular coloring agent should be followed. To extend their shelf-life, some natural colors are supplied as gelatin-encapsulated or similarly encapsulated powders and may be sealed in containers under nitrogen.
See Section 17 for incompatibilities of specific selected coloring agents; see also Woznicki and Schoneker,(4) and Walford.(
See Section 17 and Walford(9,10) for information on specific selected coloring agents.
Coloring agents are used in a variety of oral and topical pharmaceutical formulations, in addition to their extensive use in foodstuffs and cosmetic products. Toxicology studies are routinely conducted on an ongoing basis by organizations such as the World Health Organization (WHO) the US Food and Drug Administration (FDA), and the European Commission (EC). The outcome of this continuous review is that the various regulatory bodies around the world have developed lists of permitted colors that are generally regarded as being free from serious adverse toxicological effects. However, owing to the widespread and relatively large use of colors in food, a number of coloring agents in current use have been associated with adverse effects, although in a relatively small number of people.(11,12) Restrictions or bans on the use of some coloring agents have been imposed in some countries, while the same colors may be permitted for use in a different country. As a result the same color may have a different regulatory status in different territories of the world. In 2007, a study was published linking the use of six colors, tartrazine (E102), quinoline yellow (E104), sunset yellow (E110), carmoisine (E122), ponceau 4R (E124) and allura red (E129).(13) This study linked these colors with behavior issues in childen. However, after reviewing the results of the study, the European Food Standards Agency concluded that no change in legislation was needed. The lake of erythrosine (FD&C red #3), for example, has been delisted (see Section 16) in the USA since 1990, following studies in rats that suggested it was carcinogenic. This delisting was as a result of the Delaney Clause, which restricts the use of any color shown to induce cancer in humans or animals in any amount. However, erythrosine was not regarded as being an immediate hazard to health and products containing it were permitted to be used until supplies were exhausted.(14) Tartrazine (FD&C yellow #5) has also been the subject of controversy over its safety, and restrictions are imposed on its use in some countries; see Section 17. In general, concerns over the safety of coloring agents in pharmaceuticals and foods are associated with reports of hypersensitivity(15–17) and hyperkinetic activity, especially among children.(18) In the USA, specific labeling requirements are in place for prescription drugs that contain tartrazine (see Section 18) as this color was found to be the potential cause of hives in fewer than one in 10 000 people. In the EU, medicinal products containing tartrazine, sunset yellow, carmoisine, amaranth, ponceau 4R or brilliant black BN must carry a warning on the label concerning possible allergic reactions.
Pharmaceutical coloring agents form a diverse group of materials and manufacturers’ data sheets should be consulted for safety and handling data for specific colors. In general, inorganic pigments and lakes are of low hazard and standard chemical handling precautions should be observed depending upon the circumstances and quantity of material handled. Special care should be taken to prevent excessive dust generation and inhalation of dust. The organic dyes, natural colors, and nature-identical colors present a greater hazard and appropriate precautions should accordingly be taken.
Coloring agents have an almost unique status as pharmaceutical excipients in that most regulatory agencies of the world hold positive lists of colors that may be used in medicinal products. Only colors on these lists may be used and some colors may be restricted quantitatively. The legislation also defines purity criteria for the individual coloring agents. In many regions around the world there is a distinction between colors that may be used in drugs and those for food use.European Union legislation The primary legislation that governs coloring matters that may be added to medicinal products is Council Directive 78/25/EEC of 12 December 1977.(19) This Directive links the pharmaceutical requirements with those for foods in the EU. Unfortunately, the Directive makes some specific references to food legislation from 1962 that has subsequently been repealed. However the European Commission has provided guidance on cross references to the current food color legislation as contained in Council Directive 94/36/ EC.(20) In addition, the Scientific Committee on Medicinal Products and Medical Devices has delivered opinions on the suitability and safety of amaranth,(21) erythrosine,(22) canthaxanthin,(23) aluminum,(24) and silver(25) as colors for medicines. Silver was considered unsuitable. Table I gives the current position taking the above information into account. Directive 95/45/EC(7) lays down specific purity criteria for food colors and essentially replaces the provisions of the 1962 Directive. EU legislation relating to colors in medicines is clarified by the Committee for Medicinal Products for Human Use note for guidance on excipients in the dossier for application for marketing authorization of a medicinal product, EMEA/ CHMP/QWP/396951/2006.(26) United States legislation The 1960 Color Additive Amendment to the Food Drug and Cosmetic Act defines the responsibility of the Food and Drug Administration in the area of pharmaceutical colorants. Tables II, III, and IV provide lists of permitted colors.(27) The list is superficially long, but many of the coloringagents have restricted use. For the so-called certified colors, the FDA operates a scheme whereby each batch of color produced is certified as analytically correct by the FDA prior to the issuing of a certification number and document that will permit sale of the batch in question. Colors requiring certification are described as FD&C (Food Drug and Cosmetic); D&C (Drug and Cosmetic) or External D&C. The remaining colors are described as uncertified colors and are mainly of natural origin. The USA also operates a system of division of certified colors into permanently and provisionally listed colors. Provisionally listed colors require the regular intervention of the FDA Commissioner to provide continued listing of these colors. Should the need arise, the legislative process for removal of these colors from use is comparatively easy. Licensing authority approval In addition to national approvals and lists, a pharmaceutical licensing authority can impose additional restrictions at the time of application review. Within the EU this generally takes the form of restricting colors, such as tartrazine and other azo colors, in medicinal products for chronic administration, and especially in medicines for allergic conditions.
Beta-carotene; indigo carmine; iron oxides; sunset yellow FCF; tartrazine; titanium dioxide. Beta-carotene Empirical formula C40H56 Molecular weight 536.85 CAS number [7235-40-7] Synonyms Betacarotene; b-carotene; b,b-carotene; E160a. Structure Appearance Occurs in the pure state as red crystals when recrystallized from light petroleum. Color Index No. CI 75130 (natural) CI 40800 (synthetic) Melting point 1838C Purity (EU) Arsenic: 43 ppm Lead: 410 ppm Mercury: 41 ppm Cadmium: 41 ppm Heavy metals: 440 ppm Assay: 596% total coloring matters expressed as beta-carotene Identification: maximum in cyclohexane at 453–456 nm Sulfated ash: 40.2% Subsidiary coloring matters: carotenoids other than betacarotene, 43.0% of total coloring matters. Purity (US) Arsenic: 43 ppm Assay: 96–101% Lead: 410 ppm Residue on ignition: 40.2% Loss on drying: 40.2% Solubility Soluble 1 in 30 parts of chloroform; practically insoluble in ethanol, glycerin, and water. Incompatibilities Generally incompatible with oxidizing agents; decolorization will take place. Stability Beta-carotene is very susceptible to oxidation and antioxidants such as ascorbic acid, sodium ascorbate, or tocopherols should be added. Store protected from light at a low temperature (–208C) in containers sealed under nitrogen. Method of manufacture All industrial processes for preparing carotenoids are based on b-ionone. This material can be obtained by total synthesis from acetone and acetylene via dehydrolinalol. The commercially available material is usually ‘extended’ on a matrix such as acacia or maltodextrin. These extended forms of beta-carotene are dispersible in aqueous systems. Beta-carotene is also available as micronized crystals suspended in an edible oil such as peanut oil. Comments Beta-carotene is capable of producing colors varying from pale yellow to dark orange. It can be used as a color for sugarcoated tablets prepared by the ladle process. However, betacarotene is very unstable to light and air, and products containing this material should be securely packaged to minimize degradation. Beta-carotene is particularly unstable when used in spray-coating processes, probably owing to atmospheric oxygen attacking the finely dispersed spray droplets. Because of its poor water solubility, beta-carotene cannot be used to color clear aqueous systems, and cosolvents such as ethanol must be used. Suppositories have been successfully colored with beta-carotene in approximately 0.1% concentration. The EINECS number for beta-carotene is 230-636-6. Indigo carmine Empirical formula C16H8N2Na2O8S2 Molecular weight 466.37 CAS number [860-22-0] Synonyms 2-(1,3-Dihydro-3-oxo-5-sulfo-2H-indol-2-ylidene)- 2,3-dihydro-3-oxo-1H-indole-5-sulfonic acid disodium salt; disodium 5,50 -indigotin disulfonate; E132; FD&C blue #2; indigotine; sodium indigotin disulfonate; soluble indigo blue. Structure Appearance Dark blue powder. Aqueous solutions are blue or bluish-purple. Absorption maximum 604 nm Color Index No. CI 73015 Purity (EU) Arsenic: 43 ppm Lead: 410 ppm Mercury: 41 ppm Cadmium: 41 ppm Heavy metals: 440 ppm Ether-extractable matter: 40.2% under neutral conditions Accessory colorings: 41.0% Isatin-5-sulfonic acid: 41.0% Water-insoluble matter: 40.2% Assay: 585% total coloring matters, calculated as the sodium salt Disodium 3,30 -dioxo-2,20 -biindoylidene-5,70 -disulfonate: 418%. Water-insoluble matter: 40.2%. Subsidiary coloring matters: excluding provision above, 41.0% Organic compounds other than coloring matters: 40.5% Unsulfonated primary aromatic amines: 40.01%, as aniline Purity (US) Arsenic: 43 ppm 2-(1,3-Dihydro-3-oxo-2H-indol-2-ylidene)-2,3-dihydro-3-oxo1H-indole-5-sulfonic acid sodium salt: 42% 2-(1,3-Dihydro-3-oxo-7-sulfo-2H-indol-2-ylidene)-2,3-dihydro3-oxo-1H-indole-5-sulfonic acid disodium salt: 418% Isatin-5-sulfonic acid: 40.4% Lead: 410 ppm Mercury: 41 ppm 5-Sulfoanthranilic acid: 40.2% Total color: 585% Volatile matter, chlorides and sulfates (calculated as the sodium salts): 415.0% at 1358C Water-insoluble matter: 40.4% Solubility Incompatibilities Poorly compatible with citric acid and saccharose solutions. Incompatible with ascorbic acid, gelatin, glucose, lactose, oxidizing agents, and saturated sodium bicarbonate solution. Stability Sensitive to light. Method of manufacture Indigo is sulfonated with concentrated or fuming sulfuric acid. Safety LD50 (rat, IV): 93 mg/kg Comments Indigo carmine is an indigoid dye used to color oral and topical pharmaceutical preparations. It is used with yellow colors to produce green colors. Indigo carmine is also used to color nylon surgical sutures and is used diagnostically as a 0.8% w/v injection. Sunset yellow FCF Empirical formula C16H10N2Na2O7S2 Molecular weight 452.37 CAS number [2783-94-0] Synonyms E110; FD&C yellow #6; 6-hydroxy-5-[(4-sulfophenyl)azo]-2-naphthalenesulfonic acid disodium salt; 1-psulfophenylazo-2-naphthol-6-sulfonic acid disodium salt; yellow orange S. Appearance Reddish yellow powder. Aqueous solutions are bright orange colored. Absorption maximum 482 nm Color Index No. CI 15985 Purity (EU) Arsenic: 43 ppm Lead: 410 ppm Mercury: 41 ppm Cadmium: 41 ppm Heavy metals: 440 ppm Ether-extractable matter: 40.2% under neutral conditions Assay: 585% total coloring matters as the sodium salt Subsidiary colors: 45% 1-(Phenylazo)-2-napththalenol (Sudan 1): 40.5 mg/kg Water-insoluble matter: 40.2% Organic compounds other than coloring matters: 40.5% Unsulfonated primary aromatic amines: 40.01% as aniline Ether-extractable matter: 40.2% under neutral conditions Purity (US) Arsenic: 43 ppm Lead: 410 ppm Mercury: 41 ppm 4-Aminobenzenesulfonic acid: 40.2% as the sodium salt 6-Hydroxy-2-naphthalenesulfonic acid: 40.3% as the sodium salt 6,60 -Oxybis[2-naphthalenesulfonic acid]: 41% as the disodium salt 4,40 -(1-Triazene-1,3-diyl)bis[benzenesulfonic acid]: 40.1% as the disodium salt 4-Aminobenzene: 450 ppb 4-Aminobiphenyl: 415 ppb Aniline: 4250 ppb Azobenzene: 4200 ppb Benzidine: 41 ppb 1,3-Diphenyltriazene: 440 ppb 1-(Phenylazo)-2-naphthalenol: 410 ppm. Total color: 587% Sum of volatile matter at 1358C, chlorides and sulfates: 413.0% Water-insoluble matter: 40.2% Solubility see Table IX. Incompatibilities Poorly compatible with citric acid, saccharose solutions, and saturated sodium bicarbonate solutions. Incompatible with ascorbic acid, gelatin, and glucose. Method of manufacture Diazotized sulfanilic acid is coupled with Schaeffer’s salt (sodium salt of b-naphthol-6-sulfonic acid). Safety LD50 (mouse, IP): 4.6 g/kg LD50 (mouse, oral): >6 g/kg LD50 (rat, IP): 3.8 g/kg LD50 (rat, oral): >10 g/kg Comments Sunset yellow FCF is a monoazo dye. The EINECS number for sunset yellow FCF is 220-491-7.Tartrazine Empirical formula C16H9N4Na3O9S2 Molecular weight 534.39 CAS number [1934-21-0] Synonyms 4,5-Dihydro-5-oxo-1-(4-sulfophenyl)-4-[(4-sulfophenyl)azo]-1H-pyrazole-3-carboxylic acid trisodium salt; E102; FD&C yellow #5; hydrazine yellow. Appearance Yellow or orange-yellow powder. Aqueous solutions are yellow-colored; the color is retained upon addition of hydrochloric acid solution, but with sodium hydroxide solution a reddish color is formed. Absorption maximum 425 nm Color Index No. CI 19140 Purity (EU) Arsenic: 43 ppm Lead: 410 ppm Mercury: 41 ppm Cadmium: 41 ppm Heavy metals: 440 ppm Assay: 585% total coloring matters as the sodium salt Organic compounds other than coloring matters: 40.5% Unsulfonated primary aromatic amines: 40.01% as aniline Ether-extractable matter: 40.2% under neutral conditions Accessory colorings: 41.0% Water-insoluble matter: 40.2% Purity (US) Arsenic: 43 ppm Lead: 410 ppm Mercury: 41 ppm Total color: 587.0% Volatile matter, chlorides and sulfates (calculated as the sodium salts): 413.0% at 1358C Water-insoluble matter: 40.2% 4,40 -[4,5-Dihydro-5-oxo-4-[(4-sulfophenyl)hydrazono]-1Hpyrazol-1,3-diyl]bis[benzenesulfonic acid]: 40.1% as the trisodium salt 4-Aminobenzenesulfonic acid: 40.2% as the sodium salt 4,5-Dihydro-5-oxo-1-(4-sulfophenyl)-1H-pyrazole-3-carboxylic acid: 40.2% as the disodium salt Ethyl or methyl 4,5-dihydro-5-oxo-1-(4-sulfophenyl)-1H- pyrazole-3-carboxylate: 40.1% as the sodium salt 4,40 -(1-Triazene-1,3-diyl)bis[benzenesulfonic acid]: 40.05% as the disodium salt 4-Aminobenzene: 475 ppb 4-Aminobiphenyl: 45 ppb Aniline: 4100 ppb Azobenzene: 440 ppb Benzidine: 41 ppb 1,3-Diphenyltriazene: 440 ppb Solubility Incompatibilities Poorly compatible with citric acid solutions. Incompatible with ascorbic acid, lactose, 10% glucose solution, and saturated aqueous sodium bicarbonate solution. Gelatin accelerates the fading of the color. Method of manufacture Phenylhydrazine p-sulfonic acid is condensed with sodium ethyl oxalacetate; the product obtained from this reaction is then coupled with diazotized sulfanilic acid. Safety LD50 (mouse, oral): >6 g/kg LD50 (mouse, IP): 4.6 g/kg LD50 (rat, oral): 10 g/kg LD50 (rat, IP): 3.8 g/kg Comments Tartrazine is a monoazo, or pyrazolone, dye. It is used to improve the appearance of a product and to impart a distinctive coloring for identification purposes. US regulations require that prescription drugs for human use containing tartrazine bear the warning statement: This product contains FD&C yellow #5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of sensitivity to FD&C yellow #5 (tartrazine) in the general population is low, it is frequently seen in patients who are also hypersensitive to aspirin.
Titanium dioxide is used extensively to impart a white color to filmcoated tablets, sugar-coated tablets, and gelatin capsules. It is also used in lakes as an opacifier, to ‘extend’ the color. See Titanium dioxide for further information. In the EU, colors used in pharmaceutical formulations and colors used in cosmetics are controlled by separate regulations. Cosmetic colors are also classified according to their use, e.g. those that may be used in external products that are washed off after use