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International Journal of Pharmacy and Pharmaceutical Sciences

ISSN- 0975-1491 Vol 3, Suppl 3, 2011

ReviewArticle

COLORANTSTHECOSMETICSFORTHEPHARMACEUTICALDOSAGEFORMS
KRISHNAVAMSHIALLAM1*,GANNUPRAVEENKUMAR1
DepartmentofPharmaceutics,TallaPadmavathiCollegeofPharmacy,Kareemabad,Warangal,506002,Telangana,A.P.,India. Email:kv.allam@gmail.com Received:20Feb2011,RevisedandAccepted:22March2011 ABSTRACT Colorants are mainly used to impart a distinctive appearance to the pharmaceutical dosage forms. There are many types of pharmaceutical formulationswhichneedtobecoloredsuchastablets,tabletscoatings,capsules(hardgelatin,softgelatin),liquidorals,toothpastes,ointmentsand salvesetc.Thepurposeofcoloringvarieswithdifferentformulations.Coloringmayberequiredtoincreasetheaestheticappearanceortoprolong the stability or to produce standard preparations or for identification of a particular formulation. Color psychology says that, the color of the productmayalsoinfluencetheefficacyoftherapy.Thus,theprimepriorityofcolorantsistoincreasetheaestheticappearanceoftheproduct,sowe cansaythatthecolorantsarethecosmeticsforthepharmaceuticalformulations.TheclassificationofvariouscolorantsincludingFD&Ccategories, thelistsofcolorantsandtheiruses,thedescriptionaboutmajorcolorantswidelyusedintheformulationswasdiscussedhereindetail.Inmany regionsaroundthe worldthere is adistinctionbetween colors that may beused indrugs and those forfood use. This review also discusses the Status of color additives based on Code of Federal Regulations, The international regulatory status, Coloring systems for various dosage forms, Colorantblending,Handlingprecautions,Safety,StabilityandStoragedataofvariouscolorants.Legislations,whichgoverntheusageofcolorants, includeEuropeanUnionLegislationandUnitedStatesLegislation. Keywords:Colorants,Coloringagents,FD&Ccolors,PharmaceuticalColorantsandColoringsystems. INTRODUCTION Colorantsorcoloringagentsaremainlyusedtoimpartadistinctive appearance to the pharmaceutical dosage forms. We can also say that the colorants are the cosmetics for the pharmaceutical preparations,becausetheaestheticappearanceofdosageformscan be enhanced by using suitable colorants. The main categories of dosageformthatarecoloredare:tablets(eitherthecoreitselforthe coating.),hard or soft gelatin capsules: (the capsuleshell or coated beads), oral liquids, topical creams, toothpastes, ointments and salves.Theeleganceandeyeappealofacoloredproductisvaluable, especially for children whom it is often used to treat with syrups, tablets,orcapsules,toavoidinjectionsandallowtreatmentathome. Pharmaceutical preparations are colored mainly for following reasons: Increasesacceptability Unattractivemedicationcanbemademoreacceptabletothepatient bytheuseofcolor,andcolorcanalsobeusedtomakeapreparation more uniform when an ingredient in the formulation has itself a variableappearancefrombatchtobatch.Manypatientsrelyoncolor to recognize the prescribed drug and proper dosage. These attributesassistinimprovingpatientcompliance1. It is believed that brightly colored tonics, cherry red childrens cough mixtures and fleshtinted powders and ointments are more likelytobeusedbecausetheyareattractive. Foridentification It helps to identify a product in its manufacturing and distribution stages. Colors may be used for identifying similarlooking products within a product line, or in cases where products of similar appearanceexistinthelinesofdifferentmanufacturers2. Theuseof differentcolorsfordifferentstrengthsofthesamedrugcanalsohelp eliminate errors. A specific example is the anesthetic Trichloro ethylene, which may be colored blue to distinguish it from chloroformwhichitresemblesinphysicalcharacteristics. Coloring may help a doctor to recognize a previous treatment. Specific colored products become known to doctors and pharmacists,andthiscanhelpsales3. Standardpreparations Naturalcalamineisobsoleteforpharmaceuticalpurposes,becauseit is not constant in color and has been replaced by artificially prepared material tinted with a form of ferric oxide. Differences in the tint of green soft soap caused by variation in the quality of the oilsusedinitspreparationaresometimescoveredbyasuitabledye. Whenlactoseisusedasthediluentforpowderedopiumitshouldbe coloredwithCarameltogiveauniformappearancetotheproduct3. Stabilitypurpose Someoftheinsolublecolorsorpigmentshavetheadditionalbenefit when used in tablet coatings or gelatin shells of providing useful opacity,whichcancontributetothestabilityoflightsensitiveactive materialsinthetabletorcapsuleformulation.Pigmentssuchasthe iron oxides, titanium dioxide, and some of the aluminum lakes are especiallyusefulforthispurpose4. COLOR PSYCHOLOGY THE PSYCHOLOGICAL EFFECTS OF COLOR The study of color is complex, and made difficult by its variety of systems, which include the aesthetic, psychological, physiological, associative, and symbolic. This has led to discoveries of the psychophysiological attributes of color5. Color psychology says that the color of the product may also influence the efficacy of therapy. Coloreffectshaveuniversalmeaning. Colors in the red area of the color spectrum are known aswarm colorsand include red, orange and yellow (Fig.1). These warm colorsevokeemotionsrangingfromfeelingsofwarmthandcomfort to feelings of anger and hostility. Colors on the blue side of the spectrum are known ascool colorsand include blue, purple and green.Thesecolorsareoftendescribedascalm,butcanalsocallto mind feelings of sadness or indifference6. The studies were also appliedtomedications. Idealpropertiesofacolorant Nontoxicandhavenophysiologicalactivity.Freefromharmful impurities Isadefinitechemicalcompoundbecausethenonlyitscoloring powerwillbereliable,itsassaywillbepracticableandeasier. Its Tinctorial (coloring) power should be high so that only smallquantitiesarerequired.

Allametal. IntJPharmPharmSci,Vol3,Suppl3,2011,1321 Unaffected by light, tropical temperatures, hydrolysis and microorganismsand,therefore,bestableonstorage 7. UnaffectedbyoxidizingorreducingagentsandpHchanges. Compatiblewithmedicamentsandnotinterferewiththem. Ready solubility in water is desirable in most cases but some oilsolubleandspiritsolublecolorsarenecessary. Does not interferes with the tests and assays to which the preparations containing it are subject. Should not be appreciablyadsorbedontosuspendedmatter. Freefromobjectionabletasteandodour. Readilyavailableandinexpensive.

Natural coloring matters are less satisfactory than coal tar colors in manyoftheserespects. Classification A.Organicdyesandtheirlakes B.Inorganicormineralcolors C.Naturalcolorsorvegetableandanimalcolors

Fig.1:Colorwheel Organicdyesandtheirlakes Dyes Dyes are synthetic, chemical compounds that exhibit their coloring power ortinctorialstrengthwhendissolvedinasolvent 8.Theyare usually80to93%(rarely94to 99%)purecolorantmaterial.Dyes arealsosolubleinpropyleneglycolandglycerin.Theyareavailable inawiderrangeofshadesorhueswithhighercoloringpowerthan thenaturalpigments.Dyesareusuallycheaperincost. The physical properties of dyes (particle size, variation in the grinding and drying process, different suppliers) are usually not critical in terms of their ability to produce identically colored systems. The tinctorial strength of a dye is directly proportional to itspuredyecontent.Solutionsofdyesshouldbemadeinstainless steel or glasslined tanks (for minimization of dye container incompatibility) with moderate mixing and should routinely be filtered to remove any undissolved dye particles 9. Colors for clear liquid preparations are limited to the dyes. Examples include Tartrazine,Erythrosine,SunsetYellowandPatentBlueV. Lakes LakeshavebeendefinedbytheFDAasthe"AluminumsaltsofFD&C water soluble dyes extended on a substratum of alumina". Lakes prepared by extending the calcium salts of the FD&C dyes are also permitted but to date none has been made. Lakes also must be

certified by the FDA. Lakes, unlike dyes, are insoluble and color by dispersion.Consequently,theparticlesizeoflakesisverycriticalto theircoloringcapacityortinctorialstrength(Table1).Generally,the smaller the particle size, the higher the tinctorial strength of lakes due toincreased surfacearea for reflected light. Lakes are formed bytheprecipitationandabsorptionofadyeonaninsolublebaseor substrate. The base for the FD&C lakes is alumina hydrate. The method of preparation of the alumina hydrate and the conditions under which the dye is added or absorbed determines the shade, particle size, dispersability as well as tinctorial strength. Other importantvariablesarethetemperature,concentrationofreactants, finalpH,andthespeedandtypeofagitation.Theshadeorhueofa lakevarieswiththepuredyecontent. Theuseofinsolublecertifiedlakeshasseveraladvantages,namely: Thefactthattheyareinsolubleenablesthedryingstagestobe performedmorequickly. Mottling is reduced because the opacity of the system minimizesthedefectoftabletsurfacedepressions. Over coloring is not a problem because the system is opaque, hence,onlyoneshadeofcolorwillresult. Fullcolordevelopmentcanbeachievedwithafewernumberof applicationstates.Thisresultsinsignificanttimesavings. Raw material costs are also improved; many of the problems associatedwithcolorreproducibilityhavebeeneliminatedentirely.

Table1:TypicalcharacteristicpropertiesofAluminumlakes Averageparticlesize Moisturecontent Oilabsorption Specificgravity pHstabilityrange (a) 510m 1215% 4045(a) 1.72.0g/cm3 4.08.0

ASTMD28131,expressedasgramsofoilper100gofcolor. Source:Handbookofpharmaceuticalexcipients.pg.no:507.

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Allametal. IntJPharmPharmSci,Vol3,Suppl3,2011,1321 FD&Clakesareavailableinsixbasiccolors:Oneyellow,oneorange, two reds (a pinkred and an orangered), two blues (a greenblue andaroyalblue)10. Blends are available to provide m ore lake colors as needed includingbrown,green,orange,red,yellowandpurple. Lakes are largely waterinsoluble forms of the common synthetic watersoluble dyes. They are prepared by adsorbing sodium or potassium salt of a dye onto a very fine substrate of hydrated alumina, followed by treatment with a further soluble aluminum salt.Thelakeisthenpurifiedanddried11. Some examples of Aluminum lakes Brilliant Blue Lake, Sunset yellow lake, Amaranth lake, Allura red lake, Indigo carmine lake, Quinolineyellowlake. Inorganiccolorsormineralcolors Stability towards light is an important characteristic displayed by thismaterials,someofwhichhaveausefulopacifyingcapacity,e,g. Titanium dioxide. Another great advantage of inorganic colors is their wide regulatory acceptance, making them most useful for multinational companies wishing to standardize international formulae.Ondrawbacktotheiruseisthattherangeofcolorsthat canbeachievedisratherlimited. Until the discovery of coal tar dyes, mineral pigments were often used to color foods and drugs but because many have toxic effects theywere quicklydisplacedwhensyntheticdyes becameavailable. Possibly the most important application of, mineral coloring in a presentday medicament is the use of a mixture of red and yellow ferricoxidestogivecalamineafleshcolor.Titaniumdioxideisused tocolorandopacifyhardgelatincapsules. Table2:Physicalandchemicalpropertiesofsomecertifiedcolorants FD&C name RedNo.3 (Erythrosine) RedNo.40 YellowNo.6 (SunsetYellowFCF) YellowNo.5 (Tartrazine) GreenNo.3(Fast GreenFCF) BlueNo.1(Brilliant BlueFCF) BlueNo.2 (Indigotine) Chemical class Xanthine Monoazo Monoazo Pyrazolone TPM* TPM* Indigoid Light Poor V.good Moderate Good Fair Fair V.Poor Stabilityto Oxidation Fair Fair Fair Fair Poor Poor Poor pH change Poor Good Good Good Good Good Poor Tinctorial strength V.good V.good Good Good Excellent Excellent Poor Hue Solubility(g/ 100ml) Water 9 22 9 20 20 20 1.6 at 25C 25% Et.OH 8 9.5 10 12 20 20 0.5 Naturalcolorsorvegetableandanimalcolors Thisisachemicallyandphysicallydiversegroupofmaterials.Some of this colors are the products of chemical synthesis rather than extraction from a natural source, for example, carotene of commerce I s regularly synthetic in origin. The term frequently appliestosuchmaterialsisnature identical,whichinmanywaysis moredescriptive.Somewouldevenmakethecasethatanyproduct which is not a constituent of the normal diet should not be called natural.ThisviewpointwouldremovecolorssuchasCochinealand Annattofromconsideration.Asageneralization,naturalcolorsare notasstabletolightastheothergroupofcolors.Theydo,however, advantageinthattheyhaveawideacceptability.Fewmedicinally active vegetable extracts have acceptable colors of their own, especiallywhendilutedinadispensedpreparation,alargenumber ofvegetablecoloringmatterswereusedinthepast.Theonlythree leftinthecodexarecaramel,formerlycalledburntsugar(prepared by heating watersoluble carbohydrates with an accelerator until a blackviscidmassisformed),cochineal(adriedinsect),andcarmine (the aluminum lake of the coloring matter of cochineal). Other examplesfornaturalcolorantsincludeRiboflavinandAnthocyanins, PaprikaOleoresin,BeetRootRed,Annatto,Curcumin[Turmeric]. The main disadvantages with the obsolete vegetable colors were Apartfromindigo,adefinitechemicalcompound,mostwereusedas a crude drug or an extract with consequent variation in coloring power and difficulty of standardization. The tinctorial power was verylowandoftenthesecolorswerefugitiveinsolution.Inaddition, they are less readily available and more expensive than coal tar colors1213. Physicalandchemicalproperties Table 2 shows the detailed description about the physicochemical propertiesofsomemajorcolorants.

Bluishpink Yellowishred Reddish LemonYellow Bluishgreen GreenishBlue Deepblue

(TPM*TriPhenylMethane),Source:Mendesetal.,PharmaceuticalDosageFormsTablets,Vol.1,secondedition. Regulatorystatus Coloring agents have an almost unique status as pharmaceutical excipients in that most regulatory agencies of the world hold positivelistsofcolorsthatmaybeusedinmedicinalproducts.The legislation also defines purity criteria for the individual coloring agents. In many regions around the world there is a distinction betweencolorsthatmaybeusedindrugsandthoseforfooduse14. Europeanunionlegislation Directive makes some specific references to food legislation from 1962thathassubsequentlybeenrepealed. HowevertheEuropeanCommissionhasprovidedguidanceoncross references to the current food color legislation as contained in CouncilDirective94/36/EC.Inaddition,theScientificCommitteeon Medicinal Products and Medical Devices has delivered opinions on the suitability and safety of amaranth, erythrosine, canthaxanthin, aluminum,andsilverascolorsformedicines.Silverwasconsidered unsuitable15. Unitedstateslegislation The1960ColorAdditiveAmendmenttotheFoodDrugandCosmetic Act defines the responsibility of the Food and Drug Administration intheareaofpharmaceuticalcolorants. 15

The primary legislation that governs coloring matters that may be added to medicinal products is Council Directive 78/25/EEC of 12 December 1977. This Directive links the pharmaceutical requirements with those for foods in the EU. Unfortunately, the

Allametal. IntJPharmPharmSci,Vol3,Suppl3,2011,1321 Colors requiring certification are described as FD&C (Food Drug and Cosmetic); D&C (Drug and Cosmetic) or External D&C. The remainingcolorsaredescribedasuncertifiedcolorsandaremainly ofnaturalorigin. Licensingauthorityapproval ColorIndexNo.:CI19140 Yellow or Orange yellow powder. Aqueous solutions are yellow colored. Tartrazine is a monoazo, or pyrazolone, dye. It is used to improve the appearance of a product and to impart a distinctive coloringforidentificationpurposes. US regulations require that prescription drugs for human use containing Tartrazine bear the warning statement: This product contains FD&C yellow #5 (Tartrazine) whichmaycauseallergictype reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of sensitivity to Tartrazine inthegeneralpopulationislow,itisfrequentlyseeninpatientswho arealsohypersensitivetoaspirin1921. Brilliant Blue FCF: (Erioglaucine; Eriosky blue; Patent Blue AR;E133;XyleneBlueVSG)ColorIndexNo.:CI42090 It can be combined withTartrazine(E102) to produce various shades of green. It is widely used insoaps,shampoos,mouth washes22, and other hygiene and cosmetics applications. It has the capacity for inducing anallergicreaction in individuals with pre existingmoderateasthma23. Titanium Dioxide(TiO2):(Anatasetitaniumdioxide;brookite titanium dioxide; E171; Kronos 1171; pigment white 6; rutile titanium dioxide; Tioxide; TiPure; titanic anhydride; Tronox.) Color IndexNo.:CI77891 TiO2is also an effectiveopacifierin powder form, where it is employedasapigmenttoprovidewhitenessandopacitytoproducts suchaspaints,coatings,plastics,papers,inks,foods,medicines(i.e. pills,tabletsandalsointopicalpharmaceuticalformulations)aswell asmosttoothpastes24. Owing to its high refractive index, titanium dioxide has light scattering properties that may be exploited in its use as a white pigment and opacifier. The range of light that is scattered can be alteredbyvaryingtheparticlesizeofthetitaniumdioxidepowder. It is used as a white pigment in filmcoating suspensions, sugar coated tablets, and gelatin capsules. Titanium dioxide may also be admixedwithotherpigments. Quinoline Yellow SS: (Solvent Yellow 33; FD&C Yellow #11; QuinolineYellowA;YellowNo.204) ColorIndexNo.:CI47000 Itisabrightyellowdyewithgreenshade.Itisinsolubleinwater,but solubleinnonpolarorganicsolvents.QuinolineYellowSSisusedin spirit lacquers, polystyrene, polycarbonates, polyamides, acrylic resins, and to color hydrocarbon solvents. It is also used in externallyapplieddrugsandcosmetics. AlluraRedAC:(AlluraRed;FoodRed17;E129:FD&CRed40)

In addition to national approvals and lists, a pharmaceutical licensingauthoritycanimposeadditionalrestrictionsatthetimeof 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 medicinesforallergicconditions16. Thefood,drug,andcosmeticact TheFoodDrugandCosmeticActof1938createdthreecategoriesof coal tar dyes, of which only the first two are applicable to the manufactureofchewabletablets. FD&Ccolors:Thesearecolorantsthatarecertifiableforusein foods,drugs,andcosmetics. D&C colors:Thesearedyesandpigmentsconsideredsafefor use in drugs and cosmetics when in contact with mucous membranesorwheningested. External D&C colors: These colorants, due to their oral toxicity,arenotcertifiableforuseinproductsintendedforingestion butareconsideredsafeforuseinproductsappliedexternally 17. Widelyusedcolorantsinpharmaceuticals Betacarotene: (Betacarotene; carotene; ,carotene; E160a) ColorIndexNo.: CI75130(natural)andCI40800(synthetic). Itoccursinthe purestateasredcrystals whenrecrystallized from lightpetroleum.Itiscapableofproducingcolorsvaryingfrompale yellow to dark orange. It can be used as a color for sugarcoated tablets prepared by the ladle process. However, Beta carotene is veryunstabletolightandair,andproductscontainingthismaterial should be securely packaged to minimize degradation. It is particularly unstable when used in spraycoating processes, probably owing to atmospheric oxygen attacking the finely dispersedspraydroplets. Becauseofitspoorwatersolubility,betacarotenecannotbeusedto colorclearaqueoussystems,andcosolventssuchasethanolmustbe used. Suppositories have been successfully colored with beta caroteneinapproximately0.1%concentration. Indigo Carmine: (Indigotine; sodium indigotin disulfonate; solubleIndigoblue;E132;FD&Cblue#2) ColorIndexNo.:CI73015 It is a dark blue powder. Aqueous solutions are blue or bluish purple. The primary use of Indigo carmine is as a pH indicator. Indigo carmine is an indigoid dye used to color oral and topical pharmaceutical preparations and also used with yellow colors to producegreencolors. Itisusedasadyeinthemanufacturingofcapsules.Indigo Carmine is also used to color nylon surgical sutures and is used diagnosticallyasa0.8%w/vinjection. SunsetYellowFCF:(YelloworangeS.,E110;FD&Cyellow#6)

ColorIndexNo.:CI16035 Ithastheappearanceofadarkredpowder.ItisapprovedbytheUS FDA for use incosmetics,drugs, andfood. This colorant may have slightly less allergy or intolerance reaction by aspirin intolerant people and asthmatics than most of the azo dyes, although those with skin sensitivities should be careful. Allura Red has also been connectedwithcancerinmice.Notrecommendedforconsumption by children. It is banned in Denmark, Belgium, France, Germany, Switzerland,Sweden,AustriaandNorway. Quinizarine Green SS: (Solvent Green 3;Oil Green G;D&C Green#6) ColorIndexNo.:CI61565 Itisagreendye,ananthraquinonederivative.Ithastheappearance ofablackpowderwithmeltingpointof220221C.Itisinsolublein 16

ColorIndexNo.:CI15985 Itis areddishyellowpowder. Aqueoussolutions arebright orange colored. Sunset yellow FCF is a monoazo dye and is often used in conjunction with E123,Amaranth, in order to produce a brown coloring in both chocolates and caramel. At highconcentrations, Sunset Yellow insolutionwithwaterundergoes aphase changefrom anisotropicliquidto anematicliquid crystal. This occursbetween0.8Mand0.9Matroomtemperature18. Tartrazine:(Hydrazineyellow;E102;FD&Cyellow#5)

Allametal. IntJPharmPharmSci,Vol3,Suppl3,2011,1321 water.Itisusedforaddinggreenishcoloringtomaterials.Itisused incosmeticsandmedications25. IronOxides: Ironoxidesarewidelyusedincosmetics,foods,andpharmaceutical applications as colorants and UV absorbers. As inorganic colorants they are becoming of increasing importance as a result of the limitationsaffectingsomesyntheticorganicdyestuffs.However,iron oxidesalsohaverestrictionsinsomecountriesonthequantitiesthat maybeconsumedandtechnicallytheiruseisrestricted becauseof theirlimitedcolorrangeandtheirabrasiveness. Other than the above mentioned colorants, there are many more colorants were under practice; the status of these color additives wasdescribedinTable3.

Iron oxide black (CI 77499); Iron (III) oxide hydrated(CI 77492); Iron oxide red and Iron oxide yellow monohydrate are the various ironoxidesusedinpharmaceuticalpreparations. They occur as yellow, red, black, or brown powder. The color dependsontheparticlesizeandshape,andtheamountofcombined water.

Table3:Statusofcoloradditives:codeoffederalregulations(4187) Color Usedfor MaybeusedforcoloringdrugsinamountsconsistentwithcGMP MaybeusedforcoloringdrugsinamountsconsistentwithcGMP. MaybeusedinexternallyapplieddrugsinamountsconsistentwithcGMP. MaybeusedforcoloringcottonandsilksurgicalSuturesincludingsuturesfor ophthalmicuseinamountsnottoexceed2.5%byweightofthesuture. MaybeusedforcoloringdrugsinamountsconsistentwithcGMP. MaybeusedforcoloringdrugsinamountsconsistentwithcGMP. Maybeusedinexternallyapplieddrugsinamountsnotexceeding0.01%by weightofthefinishedproduct. Maybeusedforcoloringexternallyapplieddrugsinamountsconsistentwith cGMP. Maybeusedinmouthwashesanddentifricesandforexternallyapplieddrugs inamountsnottoexceed5mgperdailydoseofthedrug. Maybeusedforcoloringexternallyapplieddrugsinamountsconsistentwith cGMP Maybeusedforcoloringexternallyapplieddrugsinamountsconsistentwith cGMP Maybeusedforcoloringexternallyapplieddrugsinamountsconsistentwith cGMP MaybeusedforcoloringingesteddrugsinamountsconsistentwithcGMP. MaybeusedforexternallyapplieddrugsinamountsconsistentwithcGMP. MaybeusedforcoloringdrugssuchthatthecombinedtotalofD&CRedNo.6 and7doesnotexceed5mgperdailydoseofthedrug. MaybeusedforcoloringdrugssuchthatthecombinedtotalofD&CRedNo.6 and7doesnotexceed5mgperdailydoseofthedrug. May be used for coloring ingested drugs in amounts not exceeding 0.1% by weight of the finished product and for externally applied drugs in amounts consistentwithcGMP. MaybeusedforexternallyapplieddrugsinamountsconsistentwithcGMP. May be used for externally applied products in amounts consistent with cGMP. May be used for externally applied products in amounts consistent with cGMP. MaybeusedforcoloringdrugproductinamountsconsistentwithcGMP. MaybeusedforcoloringdrugproductinamountsconsistentwithcGMP. 17

FD&CBlueNo.1 FD&CBlueNo.2 D&CBlueNo.4 D&CBlueNo.9 FD&CGreenNo.3 D&CGreenNo.5 D&CGreenNO.8 D&COrangeNo.4 D&COrangeNo.5 D&COrangeNo.10 D&COrangeNo.11 D&COrangeNo.17 FD&CRedNo.3 FD&CRedNo.4 D&CRedNo.6 D&CRedNo.7 D&CRedNo.8 D&CRedNo.9 D&CRedNo.17 D&CRedNo.19 D&CRedNo.21 D&CRedNo.22

Allametal. IntJPharmPharmSci,Vol3,Suppl3,2011,1321 D&CRedNo.27 D&CRedNo.28 D&CRedNo.30 D&CRedNo.31 D&CRedNo.34 D&CRedNo.39 FD&CRedNo.40 D&CVioletNo.2 FD&CYellowNo.5 FD&CYellowNo.6 D&CYellowNo.7 D&CYellowNo.10 D&CYellowNo.11 MaybeusedforcoloringdrugproductinamountsconsistentwithcGMP. MaybeusedforcoloringdrugproductinamountsconsistentwithcGMP. MaybeusedforcoloringdrugproductinamountsconsistentwithcGMP. MaybeusedforexternallyapplieddrugsinamountsconsistentwithcGMP. MaybeusedforcoloringexternallyappliedinamountsconsistentwithcGMP Maybeusedforexternalgermicidalsolutionsnottoexceed0.1%byweightof thefinisheddrugproduct. May be used in coloring drugs Subject to restrictions and in amounts consistentwithcGMP Maybeusedforcoloringexternallyapplieddrugsinamountsconsistentwith cGMP In general products containing FD&C Yellow No.5 (Tartrazine) must be so labeled. The Code of Federal Regulations should be consulted for use restrictionsthatmaybeadded. MaybeusedforcoloringdrugsinamountsconsistentwithcGMP. MaybeusedforexternallyapplieddrugsinamountsconsistentwithcGMP. MaybeusedforcoloringdrugsinamountsconsistentwithcGMP. MaybeusedforexternallyapplieddrugsinamountsconsistentwithcGMP

Source:Peck.Baley.McCurdy.andBanker,PharmaceuticalDosageFormsTablets,Vol.1,secondedition. Coloringsystemsforvariousdosageforms In selecting a colorant for a given application, prime consideration should be given tothetype formulation in which thecolorantis to be incorporated. Whatever the form of colorant chosen, it should meetasmanycharacteristicsastheidealcolorant. 1. Tablets 2. Tabletcoating

2.1. Sugarcoating Thecoloringstageisoneofthemostcriticalpartsoftheoperation.It gives the tablet its color and, in some cases, its finished size. Here the success measured in terms of the elegance of thefinal product. Before the 1950s, traditional color coating for solid dosage forms was usually performed using soluble dyes as the prime colorant. This system can produce the most elegant tablet. However, many difficultiescanariseusuallyrelatedtothedyebeingsoluble. Color migration readily occurs if the drying stage after each application of color is not handled properly. This results in non uniform distribution of color or mottling. Small depressions or irregularitiesinthesurfaceofthetabletmayalsocausenonuniform color. Many smoothing coats are needed before any color can be applied.Caremustbetakentoensurethatthetabletsdonotbecome over colored. Syrups of increasing dye concentrations usually are usedtoachieveacolormatchandtocontrolmottling.Thisoperation may take from20 to 60 applications for the color to develop fully. Dyesugarcoatingisaverytimeconsuminganddelicateoperation. Lateinthe1950s,thepigmentsugarcoatingprocesswasdeveloped andsubsequentlypatentedby Arnold Nicholsonand Stanley tucke26. Thecoloringcompositionofthisinventionessentiallyanaluminum lake and a pacifier dispersed in a syrup solution. This system produced brightly colored, elegant tablets and eliminated many of theproblemsassociatedwiththestandardsugarcoatingtechniques. The dusty nature of pigments sometimes requires the use of air filtration and dust collection systems to avoid contamination of otherareasoftheplant. Today, there are a number of manufacturers who offer color matched, pre dispersed,pigment sugarcoatingconcentrates. These concentrates are easily incorporated into the bulk of the syrup coating solution. The convenience of these concentrates and easily incorporated into the bulk of the syrupcoating solution. The convenience of these concentrates and the ability of the manufacturers to reproduce color batch after batch make these productsanattractivealternativetoselfpreparationofdispersions.

1.1. Wetgranulation Dissolving watersoluble dyes in a binding solution for the granulating process is the most common approach to coloring a tablet formulating. However, during drying of the granulation, the solution,thesolublecolorsmaymigrateandifmorethanonecolor is used, the dyes may migrate at different rates. This results in an uneven coloring of the granulation, which will have a mottled appearance after compression. Some additives, such as starches, clays,andtalc,havebeenusedtoadsorbthedye,therebyreducing but not completely eliminating the migration. This entire problem canbeavoidedbyusinglakesorotherpigments.Thecolorswillnot migratebecausetheyareinsoluble.Inaddition,thelightstabilityof theproductwillbeimproved. 1.2. Directcompression Mainly of the economic reason, a growing interest in direct compression formulas has developed. The number of processing steps has been reduced. Direct compression formulation requires blendingonly;therefore,lakesandotherpigmentsareusedbecause the elimination of the wetting step prevents the effective us of solublecolors. Thedrycoloringoftabletswithpigmentsisnotwithoutproblems. Although there is little chance of color migration, poor blending of the pigments into the power can result in color specking and hot spots.Thisproblemcanbeminimizedbypreblendingthepigment withasmallpartofoneoftheotheringredientsbeforeadditionto the entire mixture to reduce pigment particle agglomeration. The ease with which the pigment can be incorporated into the formulationmaydependonthecomponentsinthemixture.

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Allametal. IntJPharmPharmSci,Vol3,Suppl3,2011,1321 2.2. Filmcoating It resolves many of the problems associated with sugarcoating. It involvestheapplication ofafilmformingpolymerontothesurface ofsubstrate(suchastablets,granules,andcapsules).Inadditionto the polymer, it also contains plasticizers and colorants, which are needed to achieve the desired properties in the final dosage form. Thepolymerandtheplasticizerareusuallydissolvedinasolventto form a coating solution in which the colorants can be dissolved or dispersed. The original filmcoating systems used organic solvents forpolymersolution. Today, aqueous systems have largely replaced the organic solvents for environmental reasons. When using organic solvents, water soluble days can be used as colorants. However, many of the same problems observed in sugarcoating may exist relating to color migration on drying of the films. Additional, because film coatings arerelativelythin,smalldifferencesinfilmthicknessontabletsmay resultinsignificantcolorvariation.Therehasbeensomesuccessin using pacified dye systems; however, these systems have been shown to have poorer light stability than pigmented coatings. The colorants of choice of these applications are lakes and inorganic pigments. In addition to providing color, pigments have been reportedtoreducemoisturediffusionthroughthefilmandimprove lightstabilityascomparedwithdye27. Commercially available predispersed color mattered pigment concentrates are recommended for use. These concentrates are availablebothinliquidandindryforms.Thedryformsmaycontain allofthecomponentsneededforatotalfilmcoatingsystemthatcan bedispersedinwaterortohersolventsdirectlyatthecoatingpan. 3. Capsules thedesiredcolorshouldbeused,becausehigherconcentrationscan resultsinadullcolor.Mostliquidproductshavedyeconcentrations of<0.001%. Ifthedyewasaddeddirectlytothebulkmixingtank,thepresenceof small amounts of undissolved material would be difficult to determine and could cause additional problems later during the compoundingprocedure30. Pigments or dyes can be used for coloring opaque liquids such as suspensions,emulsions,orimprintinginks.Innonaqueoussystems, becauseofsolubilityrestrictions,theuseofpigmentsisnecessary.If pigments are chosen as the colorants, it may be necessary to predispersed them before adding them to the final product. Concentrated dispersions in a wide variety of vehicles are commerciallyavailable. 5. Ointmentsandsalves

Both dyes and pigments can be used for coloring ointments and salves, depending on the vehicle. Pigments are preferred because they will not migrate to the surface. To incorporate the pigments into the system, it may be necessary to blend the pigment and the productonarollorointmentmill31. 6. Toothpastes

A major problem impacting the aesthetic appearance of striped toothpasteisthebleedingormigrationofcolorfromonecomponent into another. This is especially severe if one colored component is appliedtothesurfaceofawhitebase.Forthisreason,acolorantthat exhibitssubstantiallynovisiblebleedingisrequired. The high density polyethylene entrained colorants of the present inventionunexpectedlyaresubstantiallynonbleedingwhenpresent in conventional toothpaste or gel formations, particularly when contrasted with similar colorants entrained in wax and synthetic polymeric resins including paraffin wax and low density polyethylene. For example, the colorant may be entrained in the High Density Polyethylene" (HDPE)matrix using methods of encapsulation32. Blendingofcolorants Color combinations can attract or distract. So, while blending the colorants to produce different shades, thorough knowledge about theindividualcolorantistheprimerequirement33. The permitted colors do not always give satisfactory shades when used alone but most popular tints and shades can be obtained by blending. For example, Green S gives a greenish blue solution in distilledwaterandamoresatisfactorygreenisproducedbymixing it with Tartrazine as in Green S and Tartrazine Solution B.P.C. Another example, Brilliant Blue FCF can be combined withTartrazine(E102)toproducevariousshadesofgreen. The National Formulary of the United States gives information on the proportion of various water soluble and oil soluble dyes necessary to give particular hues to liquid preparations and drug powders. GenerallySpectralimagingcanbeusedtoidentifyandquantifythe colorant in tablets. Combining colorant information with other physical and chemical characteristics can provide a powerful comparisonoftablets34. Colorants should be protected during processing, use and storage,against Oxidizingagents,especiallychlorineandhypochlorites. Reducing agents, especially invert sugars, some flavors, metallic ions (especially aluminum, zinc, tin, and iron), and ascorbicacid. Microorganisms,especiallymoldandreducingbacteria. ExtremepHlevels;especiallyFD&CRed#3whichisinsoluble in acid media and Should not be used below pH 5. O. Also, effectsoffadingagentssuchasmetalsaregreatlyenhancedby eitherveryhighorlowpHvalues. 19

3.1. Hardgelatincapsules The capsules are colored primarily using FD&C or D&C colorants and sometimes an opacifying agent such as Titanium dioxide. The cleartypeofcapsuleiscoloredusingwatersolubledyes.Solutionof thesecolorsissimplyaddedtothegelatinmelt28. ThepHofthegelatinisimportantbecauseitcanaltertheshadeof thecolor.Itisalsoimportanttocontrolthetackinessofthecapsule wall because variations can change color intensity. If the active ingredientisphotosensitive,itisadvisabletouseanopaquecapsule. Opaquecapsulescancontainpigmentsordyesandanopacifier.The colorants are usually dissolved or dispersed in water, glycerin or combinationofthesevehiclesbeforeadditiontothegelatinmixture. Wall thickness is rarely a factor in determining the shade of an opaquecapsule. Recent technological advances in the area of spin printing have allowed some manufacturers to color identify capsules by printing bands of varying widths and colors on the capsule bodies through theuseofcoloredimprintinginks. 3.2. Softgelatincapsulesorsoftgels Soft Gelatin capsules (soft gels) are one piece, hermetically sealed, soft gelatin shells containing a liquid, a suspension, or a semisolid. Color used in shell has to be darker than color of encapsulating materialcolorsmaybenaturalorsynthetic29. Opacifier, usually Titanium dioxide, may be added to produce an opaqueshell,whenthefillformulationisasuspensionortoprevent photodegradationoflightsensitivefillingredients.Concentrationof opacifiermaybeupto0.5%. 4. Liquidproducts

Dyes should be used that are completely soluble in the particular solvent and at the required concentration. Many times dyes that correspondtotheflavoroftheproduct(forexample,redforcherry or yellow for lemon) will be chosen. Factors influencing the shade and stability of dyes in the liquid system must be carefully consideredaswell.ThesepropertiesarepH,microbiologicalactivity, lightexposureinthefinalproductpackage,andthecompatibilityof the dye with other ingredients. When formulating liquid products with dyes, the lowest possible concentration of dye needed to give

Allametal. IntJPharmPharmSci,Vol3,Suppl3,2011,1321 The negative activity of reducing and oxidizing agents is greatlyenhancedbyelevatedtemperatures. Exposure to directsunlightFD&CRed #40and FD&C Yellow #5 have moderate stability to light, while FD&C Blue #2 and FD&C Red #3 have poor light stability. It is important to minimize the exposure of products to direct sunlight, especiallyproductscontainingdyeblends35. suppliers to develop and test Nonabsorbable dyes, which are considered safer by virtue of their nonabsorption from the gastrointestinaltract. Stabilityandstorageconditions Pharmaceutical coloring agents form a chemically diverse group of materials that have widely varying stability properties36. Specific information for selected colors is shown in Table 4.

Concerns still persist about the safety of absorbable dyes despite Completedstudiesdonesofar.Thishasleddyemanufacturersand

Table4:Stabilitypropertiesofsomemajorcolorants Heat Color BrilliantblueFCF Good IndigoCarmine Good FD&Cgreen3 Good Erythrosine Good AlluraredAC Good Tartrazine Good SunsetYellow Good D&Cyellow#10 Good Light Moderate VeryPoor Fair Poor Moderate Good Moderate Fair Acid VeryGood Moderate Good Insoluble Good Good Good Good Base Moderate Poor Poor Good Moderate Moderate Moderate Moderate Oxidizingagents Moderate Poor Poor Fair Fair Fair Fair Poor Reducingagents Poor Good VeryPoor VeryPoor Fair Fair Fair Good

Source:RaymondCRowe,PaulJ,SheskeyandSianCOwen,HandbookofPharmaceuticalexcipients. 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 theirlowtoxicity37.Lakes,inorganicdyes,andsyntheticdyesshould bestoredinwellclosed,lightresistantcontainersatatemperature below30C. Formostnaturalandnatureidenticalcolors,thestorageconditions are more stringent and a manufacturers recommendations for a particular coloring agentshouldbefollowed. To extendtheirshelf life, some natural colors are supplied as gelatinencapsulated or similarly encapsulated powders and may be sealed in containers underNitrogen. To compensate for losses due to fading and other dye loss during processingandstorage,someformulatorsaddaslightexcessofdye atthebeginning.Thisapproachshouldbecautiouslyemployedsince onecanobtainunattractiveshadeswhentoomuchcolorisaddedat the beginning in an attempt to provide for timedependent or processing color loss. Regulations covering all aspects of colorants including their procedures for use, provisionally and permanently certified and uncertified color additives, and use levels and restrictions for each coloring additive are covered in the Code of FederalRegulations21CFRparts70through82. Safety Toxicology studies are routinely conducted on an ongoing basis by organizationssuchastheWorldHealthOrganization(WHO),theUS FoodandDrugAdministration(FDA),andtheEuropeanCommission (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,althoughinarelativelysmallnumberofpeople 3839. AlluraRedACisnotrecommendedforconsumptionbychildren.Itis bannedinDenmark,Belgium,France,Switzerland,andSweden40. The lake of erythrosine (FD&C red #3), for example, has been delisted in the USA since 1990, following studies in rats that suggestedthatitwascarcinogenic.This delistingwasasaresultof 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 supplieswereexhausted41. Tartrazine (FD&C yellow #5) has also been the subject of controversy over itssafety, and restrictionsare imposed onits use in some countries; In general, concerns over the safety of coloring agentsinpharmaceuticalsand foods areassociatedwith reports of hypersensitivity4244 and hyperkinetic activity, especially among children45.IntheUSA,specificlabelingrequirementsareinplacefor prescriptiondrugsthatcontainTartrazinasthiscolorwasfoundto bethepotentialcauseofhivesinfewerthanonein10000people.In the EU, medicinal products containing Tartrazine, Sunset yellow, Carmoisine,Amaranth,Ponceau4RorbrilliantblackBNmustcarry a warning on the label concerning possible allergic reactions. The useofTartrazineisbannedinNorway. Handlingprecautions Pharmaceutical coloring agents form a diverse group of materials and manufacturers data sheets should be consulted for safety and handlingdataforspecificcolors. In general, inorganic pigments and lakes are of low hazard and standard chemical handling precautions should be observed dependinguponthecircumstancesandquantityofmaterialhandled. Special care should be taken to prevent excessive dust generation andinhalationofdust. Theorganicdyes,naturalcolors,andnatureidenticalcolorspresent agreaterhazardandappropriateprecautionsshouldaccordinglybe taken46. CONCLUSION The colorants works as the cosmetics for the pharmaceutical formulations, thus, selection of appropriate colorant for a specific pharmaceutical dosage form plays an important role in manufacturing of the pharmaceutical dosage forms. Since most of the colorants are extremely effective, only minute amounts are necessary to produce the desired color. The Color consistency is important as it allows easy identification of a medication and responsibleforthedosageformsaestheticappearance. As we can see, selection of colorants for use in global drug developmentcanbeverycomplicatedandtimeconsuming.Withthe differences in colorant regulations worldwide and the need for variousperformanceattributesbasedonthedosageform,thereare numerous considerations that must be assessed. Restrictions or bansontheuseofsomecoloringagentshavebeenimposedinsome countries, while the same colors may be permitted for use in a different country. As a result the same color may have a different regulatorystatusindifferentterritoriesoftheworld.

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Allametal. IntJPharmPharmSci,Vol3,Suppl3,2011,1321 Therefore it is important that appropriate expertise be consulted before finalizing colorant selection to help prevent future developmentorregistrationproblem. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. DavidR.Schoneker,ColoringAgentsforUseinPharmaceuticals Colorcon,Inc.,WestPoint,Pennsylvania,U.S.A. Peck. Baley, McCurdy and Banker, Pharmaceutical Dosage FormsTablets,Vol.1,secondedition:116117. GraceFrimpongMRS,Investigatingthesuitabilityof HIBISCUS SABDARIFFA CALYX extract as Coloring agent for Pediatric syrups.July,2008:44 Rowe RC. The opacity of tablet film coatings. J Pharm Pharmacol1984;36:569572.PubMed. Aspects of Color, Frank Vodvarka, Associate Professor of Fine Arts,LoyolaUniversityChicago. KendraCherry,About.comGuide.ColorPsychologyHowColors ImpactMoods,Feelings,andBehaviors. 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