Cosmeticcreamspotencyandstoragetime:theliteraturesurveydiscoveringthecorrelationofstoragetimetodegradationofcosmeticformulations

Abstract:Thequicklygrowingmarketofcosmeticproductsdemandsnewformulationswithnewactiveingredientswhilemaintainingapromptandeffectiveproductdevelopmentlifecycle.Whileproductschemicalandclinicaltestsmaytakesignificanttime,cosmeticcompaniesusesimplifiedapproachesforproductdevelopmentinordertoguaranteethestabilityofphysicalappearanceandsafety.Butatthesametimedatarelatedtothechemicalstabilityandpotencyofcosmeticproductsremainsveryscarce.Thisreviewsummarizesinformationavailablerelatedtodegradationprocessesincosmeticcreamsanddiscussestherisksoflongstoragebeforeusage(mainlycosmeticemulsions).Specificattentionisputonactiveingredientssuchasvitaminsandessentialoils.

Conclusion:Cosmeticcreamslosetheirpotencywithtimeevenwhenproperlystoredintightlyclosedcontainers.Thisprovidestheevidencethatbrandsneedtodecreasetheirproductsshelflife,searchforstableformulationsorfindotherwaystominimizeproductdegradationandmaintainitspotency.

Keywords:Cosmetics,cream,degradation,cosmeceuticals,vitamins

Introduction

Thequicklygrowingmarketofcosmeticproductsdemandsnewformulationswithnewactiveingredientswhilemaintainingapromptandeffectiveproductdevelopmentlifecycle.Whileproductschemicalandclinicaltestsmaytakesignificanttime,cosmeticcompaniesusesimplifiedapproachesinordertoguaranteephysicalappearancestabilityandsafety.Buthowdoesthisaffecttheendconsumerproductanditspotency?

Nowadays,customersarewellawareofmanydifferentingredientsthatareusedincosmeticformulations,andunderstandtheireffectsandfunction.Cosmeticproductsthatcontainchemicalsproducts with bioactive ingredients purported to have medical benefits arecategorizedas“Cosmeceuticals”.

Thetermcosmeceuticalwascreatedmorethan25yearsagotodefineproductswithactivesubstancesthatcanneitherbecategorizedascosmeticsnordrugs.ThistermhasnomeaningunderUSlaw.Theseproductsarefoundinmanyforms,includingvitamins,peptides,growthfactors,andbotanicalextracts.Cosmeceuticalsthatcontaintopicallyappliedvitaminshaveanincreasingroleinskincare.Therearestillmanycontroversialpointsregardingtheingredientsusedincosmeceuticalproducts;amongthem,mechanismsofaction,optimalconcentration,biologicallyactiveform,formulationstability,penetration,andretentionwithintheskin.Althoughtestsareavailabletoanswersomeofthesequestions,itcanbespeculatedthatattimesthereislittleinterestinsuchdata,giventhatcosmeceuticalproductsarenotregulatedandareusuallywell-acceptedbyconsumers.Thequestionremainswhetheritispossibletodeliveradequatedosestotheskininvivoandtoproduceclinicalorhistologiceffects.Itisimportanttoevaluatethesenewproductswithacriticalandcarefulmethodology,givingconsiderationtointendedproductuseandthedesignofavailablestudiessupportingproductuse.Then,onecandecideiftheproductisusefulasamainoradjuvanttreatmentforagingskin[1].

Cosmeticproductsneedtobesafeforconsumersduringtheirentireshelflifewhichisestablishedbytheproducer.Whilethecompositionofcosmeticsisregulated,therearenoexplicitlegalrequirementstoperformstabilitytesting.Mostcosmeticformulationsaretestedwithemphasisonmicrobiologicalstability,whereastheirchemicalstabilityisonlymarginallyinvestigated.Alterationofcosmeticscanoccurbymigrationofpackagecomponents,thedecompositionofingredientsortheformationofcompoundsinvolvingreactivecontaminants.Withoutaninvestigationofthe

chemicalstability,theproducercannotbesurethathisproductissafefortheestimatedshelflife[2].

Toensurethatthevariousfunctionsofcosmeticsarerealized,thefirststageistoobservewhetherornotthereareanychangesintheirphysicalandchemicalproperties.Chemicalchangesincludecolorchange,colorfading,fragrancechange,staining,crystallization,etc.Physicalchangesincludeseparation,sedimentation,aggregation,blooming,sweating,gelling,unevenness,evaporation,solidification,softening,cracking,etc.Thesephenomenanotonlyhaveagreateffectonusability,butalsomakecosmeticsunattractiveanddamagetheirimage.Generally,productqualitymustbeguaranteeduntilitiscompletelyusedbytheconsumer,andmanufacturersshouldfocusonthisbaseassumptionwhileconductingtheirresearchonimprovingtheirproductlevel.Guaranteeingincreasedproductlifegreatlyhelpsinachievingtheaforementionedbaseassumption.

Somepharmaceuticalagentsareeasilydegradedbyatmosphericoxygen,andtheyareoftenconsideredtobechemicallyunstablecompounds.Forexample,vitaminsA,B1,B2,B6,C,etc.areallunstable.Moreover,inacosmeticsystem,thesecompoundsmaybeincompatiblewithothercompoundstheyaremixedwith.SomemayalsobeaffectedbychangesinpH.

Toensurethestabilityofpharmaceuticalagentsusedinaproduct,itisalsoveryimportanttounderstandtheeffectsofotheringredientsused,andalsotheeffectsofpH,temperature,andincompatibleorreactivecompounds,etc.[3].

Cosmeticproductsaregenerallyformulatedandtestedforashelflifeof1-3yearsundernormalstorageconditions,dependingonaproduct'scomposition,packaging,preservation,andotherfactors.Consumersshouldbeawarethatshelflife(expirationdates)aresimply"rulesofthumb,"andthataproduct'ssafetymayexpirelongbeforetheexpirationdateespeciallyifnotstoredproperly[4].

Toensurethemaximumdurabilityofcosmeticproducts,theyshouldbestoredinacool,dryplace,awayfromdirectsunlightandwiththelidsfirmlyclosed.Ontheotherhand,natureandphysicochemicalpropertiesofactiveingredientsandexcipientsalsoinfluenceproductstability.Manufacturingprocedure,closure,container,andthenatureofpackingmaterialplayanimportantroleinmaintainingthestabilityofpreparations[5].

Degradationprocessesandfactorsinfluencingstability

Typicalcosmeticcreamisnotasimpleformulation.Itisanemulsionintheformofoilphaseinwater(o/wemulsion)orwaterinoil(w/oemulsion).

Figure1–Pictureofasimpleo/wemulsion

Ononehandthetwo-phasesystemprovidesincreasedphysicalstabilityandproperties,allowingfordissolutionofbothwaterandoil-solubleingredients.Ontheotherhandthiscomplexmixturepresentsrisksforingredients.Themajorrisksareexposuretofactorssuchasmoisture,pH,light,microbialcontaminationandothers.Thesefactorsmayleadtodegradationofingredientsthusleadingtodecreaseintheirpotencyandtheoverallcosmeticproductefficacy.

Figure2–Simplevisualizationofdecompositiontimeforseveralgroupsofingredients[4]

Factorsknowntoinducechemicaldegradationincreams:

• Hydrolysis• Photodegradation(exposuretolight)• Temperature• pHvariations• Remainingoxygen• Microbialcontamination• Ingredientsincompatibility

Besidehumanhealthpreoccupation(modificationofthenaturalskinflora,allergiesordangerousrisksofinfectiontotheconsumer),microbiologicalcontaminationmayleadtochemicalchangesthataltertheproductandlimititsshelflife.Maintaininganoptimalmicrobiologicalproductstatefromproductionthroughusageisarealchallengeformanufacturers.Whileonecommonlyusedapproachistheuseofpreservatives,additionalrisksarise:

1) Companiesstruggletofindtheoptimalamountofpreservativesforincreasedshelflifeandtendtooverusethemwhichleadstounnecessarycustomerexposuretoextrachemicals(suchasbenzalkoniumchloride)ortorisksofpreservativesdegradationandformationoftoxicsubstances(suchasformaldehyde).

2) Productsareinsufficientlypreserved.Inthiscaseactiveingredientsandbaseemulsionsareanutritionalsourceforbacteria.Thisleadstoadecompositionoftheactiveingredientsandaccumulationoftoxicmicrobialproducts.

Manufacturersattempttoincreaseproductsshelflifedirectlyimpactstheirchemicalstability.Cosmeticproductsarenotregularlytestedaspharmaceuticalproducts,andproductsareregularlyrecalledfromthemarketduetomicrobiologicalorchemicaldegradation[6,7].Screeningdonebyindependentlabsalsoshowedmicrobialcontamination,suchasinrecentresearchfromPolandinwhich6cosmeticproductsweretestedand8microbialstrainswereisolatedfrom3products[8].

Othersideeffectsrelatedtomicrobialcontaminationareduetodifferentstorageconditions.Recentstudiesincountrieswithhotandhumidclimatehaveshownthatproductsaremoresusceptibleto

microbialcontaminationevenwhilestoredinsealedcontainers,seeexamplesfromLibya[9],Bangladesh[10],orPakistan[11].InPakistanabout16.7%ofthetestedsampleswereheavilycontaminated(morethan1000CFU/g).

Thoughmicrobialcontaminationanddegradationareconsideredtobemanageable,theydirectlyaffectingredientspotency.

Degradationofingredients

Vitamins

Vitaminsareconsideredtobethemostunstableingredientsusedincosmeticformulations.Thoughtheirstabilityisn’tthoroughlyevaluated,severalwell-designedstudiesshowedthatVitaminCandVitaminAshelflifewhenusedincosmeticcreamstobeseveralmonths.Whichmeansthatbythetimetheconsumerusestheproduct,suchvitaminsmightbedecomposed.

MoreresearchisavailableonvitaminsA,C,andEduetotheirpopularityinthetreatmentofagingskinandtheprotectionofagainstUV-induceddamage.However,esterifiedvitaminderivatives(e.g.,retinylpalmitate,ascorbyltetraisopalmitate,andtocopherylacetate)withimprovedstabilityhavebeenpreferentiallyusedintopicalformulations.Butevenintheiresterforms,thesevitaminscanhavelowshelflife,asshownbyGuaratinietal.[12]Theauthorsevaluatedagel-creamformulationcontainingvitaminApalmitateandvitaminEacetateandobservedashelflifeof77days,characterizedbyafirst-orderdegradationreactionofthevitaminAderivative.

Figure3-Quantificationof(A)retynilpalmitateand(B)tocopherylacetateexpressedaslogsofconcentrationvaluesover

timemaintainedatvariousconditions[12].

VitaminA

Esterbondshydrolysisisoneoftheoften-observeddegradationreactions.Cleavageofesterbondsmaynotbeanissueiftheproducedchemicalsaresafe.Havingsaidthat,itstillaffectstheingredientspotencywhichisdecreasedovertime.OneofthearticlesstudiedthechemicalstabilityaspectsofVitaminAandEestersfoundthatactualshelf-life(determinedwhen15%ofactiveingredientsweredegraded)wasn’tsufficient.Theyfoundthatonly85%ofVitaminAremainedintheformulationafter77daysofstorageat25°C,21daysat37°C,and14daysat45°C.Thus,asproposedinthisstudy,togetthemostoftheVitaminAitisadvisedtousethecreamwithin1-2monthsaftermixing[12].

VitaminC

VitaminC(ascorbicacid)isapotentantioxidantwithseveralapplicationsinthecosmeticandpharmaceuticalfields.However,thebiggestchallengeistomaintainitsstabilityandimproveitsdeliverytotheactivesite.

Ascorbicacidisanaturallyoccurringantioxidant,effectiveintreatmentandpreventionofphotoagedskinandhelpfulinskindepigmentationandcollagensynthesis.Chemicalandphotochemicaloxidationareconsideredtobemajorcauseofdegradationincreamscontainingascorbicacid,italsoshowssensitivitytowardsairandlight.L-dehydroascorbate(DHA),2,3-L-diketogulonate(2,3-DKG),L-erythrulose(ERU),andoxalatearetheprimarydegradationproductsofascorbicacid[5].

Twoderivativesofascorbicacid,i.e.,ascorbylpalmitateandsodiumascorbylphosphate,whichdifferinstabilityandhydro-lipophilicpropertieswerestudiedbyP.Spiclin,M.Gasperlin,V.Kmetecin2001.Ascorbylpalmitateinhigherdosagewasmorestabletotime,butlightanddissolvedoxygeninducedoxidation.Onthecontrary,sodiumascorbylphosphatewasstableinbothmicroemulsionstype.Sodiumascorbylphosphatewasrevealedtobeconvenientasanactiveingredientintopicaldosageform.Inthecaseofascorbylpalmitate,long-termstabilityinselectedmicroemulsionswasnotadequate[13].

Thephysicochemicalstabilityofascorbicacidindifferentwater-in-oil(w/o)creamsduringstoragewasassessed.ThestudyexaminedtheeffectofmediumpHandviscosityanduseofdifferentexcipientsonitsphysicochemicalstability.

Severalwaterin-oil(w/o)creamformulationswithascorbicacid(AA)werepreparedatpH4-6usingdifferenthumectantsandemollients.Creamswereplacedinthedarkat30°Cforaperiodofthreemonthswhilepreformingstabilitystudiesforascorbicacidtochecklossandchangeinphysicalfeatures.Resultsrevealedthatthecream’spHinfluencedthestabilityofAAasitsdegradationraterosewithriseinpHbyfirst-orderkinetics.ThestabilityofAAwasimprovedastheviscosityofthemediumincreased.Creamsthatshowedthehighestratesofdegradation(i.e.,atpH6)werecomparedtocreamswiththesamepHbutbyaddingcitricacidasastabilizingagent.CitricacidwasfoundtodecreasedegradationratesofAAinallformulations[14].

Itwasobservedthateventhoughcreamformulationswerekeptinthedark;AAunderwentaerobicoxidationandultimatelyphotolyticreactions.Spectrophotometricresultsshowedthattherateofoxidativedegradationinthepresenceoflightisaboutseventytimesfasterthanthatobservedinthedark.Pharmaceuticalcreamsshowcomplexbehaviorsuchasformationofdegradationproductsthatmaybetoxicornontoxicinnature,breakdownofcreambases,andphysicalandchemicalinstabilitymakingpreparationsinappropriateforuse[5].

Otherauthorsobservedthatthewater-solublevitaminCderivative,magnesiumascorbylphosphate,wasmorestablethanascorbylpalmitate(lipidsolublederivative),whichwasconsideredveryunstable,duetothelipophilicesterinposition6thatdoesnotprotectthisvitaminfromdegradation.Anotherstudyshowedthatmagnesiumascorbylphosphatehadamediumshelflife(7months),whichconfirmedthecapabilityofthephosphategrouptoprotecttheenediolsystemfromhydrolysis,evenwhenitisincludedincosmeticformulations.Inaddition,SegallandMoyanoshowedthatascorbylesters,sodiumascorbylphosphate,andmagnesiumascorbylphosphatearemorestablethanascorbylpalmitate,sinceafter6months,theyfoundaremainingconcentrationof20%ofascorbylpalmitateincomparisonto70–80%oftheotherderivatives[15].

Figure4-StabilityofvariousVitaminCformsincosmeticformulations[15]

TheamountofAAwasfoundtodecreaseovertimeinallformulationsduetotheoxidationofthevitamin.The%lossofAAwasfoundtobedifferentineachformulationwhichindicatestheroleofpHandvariousformulationfactorsonthedegradationofAA.Allcreamsstoredfor3monthswerefoundtoretainAAintherangeofaround9–44%withthehighestvaluesofr(~44%)observedinformulationatpH4whereasthemaximumloss(~90%)hasbeenobservedinformulationatpH6(Fig.below).Thesevaluesshowbetterstabilitythanthosepreviouslyreportedforw/oemulsionsofAAcontainingsoybeanandmoringaoilwherethervaluesof50%and30%wereobservedafter30daysofstorageat4°Cand25°C,respectively[16,17]

Figure5-Changeinretentionrate(r)ofAAwithtimeintwow/ocreamformulations(●)and(▲)atpH4–6[14]

ImprovedstabilityforVitaminsincombination

Anotherresearchgroupfoundthatcombiningdifferentvitaminsisabout2-foldmorestablethanVitaminAbyitself[18].VitaminAlost15%ofitscontentafter60daysandgainedanadditional60daystotaling120dayswhencombinedwithothervitamins.

Formulationscontainingvitamins,bythemselvesorincombinationwithothervitamins,presenteddifferentdegradationkineticsforvitaminsA,CandE.Whenthesevitaminswerecombinedinoneformulation,theirdegradationratewasslightlylowerthanwhentheywereindividuallyused.The

shelflifeofvitaminscontainedincombinationwas120,318and1,116daysforvitaminA,CandE,respectively.Forsinglevitaminsthevalueswere61,173and757forvitaminA,CandE,respectively.Thesameresultswereobtainedexperimentallyinformulationsmaintainedatroomtemperature,whichvalidatestheacceleratedmethodemployedforchemicalstabilitydeterminations.[18]

Vitaminderivatives Shelf-life(days)Alone Incombination

Retinylpalmitate 61 120Ascorbyltetraisopalmitate 173 318Tocopherylacetate 757 1116

OneofthestudiesprovidesevidencethatshelflifeofgelcreamformulationswithsiliconescontainingcombinationsofvitaminApalmitateandvitaminEacetatewereverylowandthattheadditionoftheantioxidantDL-alpha-tocopherolenhancedtheperiodto77days.OtherauthorsobservedthattheadditionofantioxidantssuchasBHT,RonoxanA®,alpha-tocopherolandglutathioneincreasedtheshelflifeofformulationscontainingvitaminApalmitate[19].

Inadditiontothesynergisminefficacystudiesreportedintheliterature,thestudiessuggestpositiveinteractionbetweentheliposolublevitaminsA,CandE.Asobservedintherheologicalstudy,combinedvitaminderivativesdidnotalterthephysicalcharacteristicsofthevehiclebutratherenhancedthestabilityoftheformulationbyincreasingtheshelflifeofeachcomponent.Theseresultsareconsistentwiththeonesthatobservedabetterstabilityofvitaminsincombination[18].

Essentialoils

Essentialoilsareoftenusedincosmeticformulationsbecauseofthewidespectrumoftheirbiologicalactivity,includinganti-inflammatory,antibacterialandotherskineffects.However,withanumberofbeneficialpropertiestheyalsopossessanumberofrisksforcosmeticformulations.Theissuewithessentialoilsisthattheyareoftenaddedintheformofacrudemixturewhichincludesawiderangeofsinglechemicalswithdifferentproperties.Duetotheirstructuralrelationshipwithinthesamechemicalgroup,essentialoilcomponentsareknowntoeasilyconvertbyoxidation,isomerization,cyclization,ordehydrogenationreactions,triggeredeitherenzymaticallyorchemically.[20]

Forinstance,themaincomponentsoflavenderoilarelinaloolandlinalylacetate,whichareeasilyoxidizedwhenexposedtooxygen.Thishappenswhentheoilisappliedtotheskin.Theoxidizedfragranceincreasestheirritancyontheskin.Whilefreshlypreparedcosmeticmixturecontainsunchangedcomponents,longtimestoragewillleadtodegradationofdelicateessentialoilingredientsevenwhennotexposedtooxygen.

Temperature,light,andoxygenavailabilityareknowntohaveacriticalimpactonessentialoilsintegrity.

Figure6-Proposedoxidationschemeofterpenoids.(A)Dehydrogenationandpossiblehydrogenrearrangements.(B)Autoxidationpathwayleadingtohydroperoxidesandsubsequentdegradationintosecondaryoxidationproduct[20]

Figure7-Mainmechanismofautoxidationandsomepossiblebranchingreactions[20]

Light.Ultraviolet(UV)lightandvisible(Vis)lightareconsideredtoaccelerateautoxidationprocessesbytriggeringthehydrogenabstractionthatresultsintheformationofalkylradicals.However,compositionalchangesproceededconsiderablyfasterwhenilluminationwasinvolved.Specifically,monoterpeneswhohavebeenshowntorapidlydegradeundertheeffectoflight.[20]

Veryrecently,TurekandStintzingshowedthatessentialoilsweremodifiedbytheeffectoflight,however,varyingbytheirsource,theessentialoilsrespondeddifferently:Whileessentialoilfromthymedidnotaltermuch,rosemaryoilturnedouttobeverysusceptibletoimitateddaylightwhichledtoachangeinitschemicalcomposition[20].

Teatreeoilcompositionchangedwhenexposedtooxygen,hightemperature,lightandhumidity.Theantioxidantcompoundsα-terpinene,ɣ-terpineneandterpinolenewereconvertedtop-cymene.Asitissensitivetooxidation,theEuropeanCosmeticsAssociationrecommendedthatthepresenceofteatreeoilincosmeticproductsshouldnotexceed1%andthattheproductshouldbepackedtominimizeexposuretolight[21].

Generally,standaloneessentialoilsthatareproperlystored(lowtemperature,darkplace)haveashelflifeofabout2-3years.Whenanessentialoilisaddedtoacreamformulationitisexposedtofactorssuchasmoisture,remainingoxygenandimproperpH.Overtime,theseconditionsdegradetheessentialoilandreduceitspotencyandcouldfurthercauseirritationoranallergicreactionduetoitseffectontheformulation.

Peptidesandproteins

Itiswellrecognizedthatproteinsandpeptidesincosmeticsprovidearangeofbeneficialeffectsspecificallyintopicalformulations.Collagenisthemainfibrousproteinofconnectivetissueinanimalsandisthemostabundantproteininmammals.Collagenisusedinavarietyofproductsincludingskinandhairproducts.Mostofthepeptidesusedasingredientsinhealth-promotingfoods,dietarysupplements,pharmaceutical,andcosmeceuticalpreparationsareobtainedbychemicalsynthesisorbypartialdigestionofanimalproteins.Thismakesthemunattractivetoconsumersduetorisksassociatedwithsolventcontaminationortheuseofanimalderivedsubstances.Plantandmicroalgaederivedpeptidesareknowntobeselective,effective,safe,andwelltoleratedonceconsumed,thustheyhaveagreatpotentialforuseinfunctionalfoods,drugs,andcosmeticproducts[22].

Whilethereareanumberofissuesrelatedtotheuseofanimal,plantorsyntheticpeptides(animalorigin,potentialallergens,varyingcomposition)theyarethoughttoberelativelystablewithnomajorchemicalrisks[23].Peptidehydrolysisisthoughttobeoneofthemajordegradationrisksforpeptidesandproteins,butincosmeticformulationsthisisn’tthoughttobeasignificantfactor[24].

Hyaluronicacid

Hyaluronicacidiscommonlyusedincosmeticproducts.Hyaluronicacid(hyaluronan,HA)isalinearpolysaccharideformedfromdisaccharideunitscontainingN-acetyl-d-glucosamineandglucuronicacid.Itsmolecularmasscanvarybetween2x10^5and10x10^6Daanditsphysiologicalpropertiesarestronglyinfluencedbyitspolymericandpolyelectrolytecharacter,aswellasbytheviscousnatureofitssolutions[25,26,27].

Degradationofhyaluronicacidasasingleingredientiswellstudied.Itsdecompositionisknowntobeinducedbymetalions(morespecificallycopper),enzymatichydrolysis,oxidationandelevatedtemperatures.Unfortunately,thereisnosufficientevidencethatshowshowhyaluronicacidisdegradedincosmeticformulations[28].

ScientistshaveshownthatHyaluronicacidphysicallychangesovertime.Severalformulationswithdifferentcompositions,viscosityandotherparameterswereanalyzedfortheirphysicalstabilitybyPolishscientistsusingopticalmethods.TheyobservedthemigrationphenomenonofparticlesinsampleC(softointmentwithHA),andflocculationphenomenoninsampleD(ointmentbasedonlanolin).Thesampleslosttheirstabilityovertime.Backscatteringpropertieschangewithtimewasobserved(seefigurebelow)withmajorchangesofphysicalpropertiesatday20.Theauthorsconcludedthatmanufacturersneedtodevelopmorestablemixturesordeclareshortershelflife.Apartfroma25°Ctemperature,itisnotclearwhatconditionswereusedwhilestoringthesamplesanditwasnotconcludedhowthepotencychangedovertime[26].

Figure8-KineticsofflocculationforsamplesA,BandD[26]

Generallyspeaking,hyaluronicacidcanbedescribedasarelativelystableingredientincosmeticformulationsbutoxidationprocessesinducedbyotheringredientscanleadtoitsdecomposition.

Chemicalincompatibilitybetweeningredients

Chemicalincompatibilitybetweeningredientscanleadtoadecreaseinproductpotency.Thechemicalincompatibilityleadstochangesinchemicalnature,solubility,absorptionandtherapeuticresponse.Therefore,duringtheformulationofnewproductsorthereformulationofexistingones,theinteractionbetweenactivemarkersofvariousplantextractsandcommonlyusedexcipientsshouldbecarriedoutthoroughly.However,nouniversallyacceptedprotocolisavailableforevaluatingthecompatibilityofproductswithdifferentexcipients.Assessmentofpossiblecompatibilitybetweenanactivecomponentanddifferentexcipientsalongwiththeevaluationofthermalstabilityarecrucialpartsofanormalstudypriortothefinalformulation.

Theincreasinginterestintheuseofplant-basedformulationsisleadingtoafast-growingmarketforAyurvedic,nutraceuticalandpolyherbalformulations.Unfortunately,thequalityofamajorityofthemremainsuncontrolled.Despitetheadvancesincosmeticchemistrywhichhaveallowedscientiststoavoidmanysuchissues,incompatibilitycanstilloccurfornewandpoorlystudiedingredientssuchaskalmegh(Andrographispaniculata)andkutki(Picrorhizakurroa)extractsinIndia.Thestudysuggestedthattheactivemarkersofkutki(kutkosideandpicroside-I)werefoundtobedegradedinthepresenceofthekalmeghextract[29].

AloeVera

ItalianresearchersstudiedthestabilityofAloeVeracomponentsresponsibleforbiologicalactivity.Namely,theyexaminedthestabilityofbeta-polysaccharidesandaloinincommonhomemadepreparations(grapebrandyandhoney)orcommercialpreparationswithorwithoutantioxidant(ascorbate,0.05%or0.005%)orantimicrobialagent(sodiumazideorsodiumbenzoate).Sampleswerestoredfor65daysinsealedglasstubesinthedark.Sampleswithaddedascorbatewerestoredat+4°Cor+22°C.ThesampleswereanalyzedatvarioustimepointsusingLC-MS/MStomeasureanthraquinonesandacemannancontent(twocomponentsofaloin).PolysaccharidesweremeasuredbyUV/VisspectroscopyafterbindingwithCongoReddye.Thetimestodecreasefrom100%to50%(DT50)andto10%(DT90)werecalculated.Atroomtemperature,thealoinDT50inwholeleafhomogenatewas11-20days,whileat+4°CtheDT50was14-26days.Inthecommercialpreparationstoredat+4°C,theDT50was108daysandDT90was360days.Thebeta-

polysaccharidesweremoreunstable.InleafgelatroomtemperaturetheDT50was2-3daysandDT90was7-10days.InthecommercialpreparationtheDT50was44daysat+4°Cand12daysat22°C,andtheDT90was148daysand41days,respectively.Thus,antimicrobialagentsorantioxidantsdidnotsignificantlyaffectthestabilityofthealoinorpolysaccharides;however,temperaturehadamajoreffect.Thecommercialpreparationwasmorestable,butstilldegradedevenat+4°C.[30]

Discussionandconclusions

Accordingtothedatacollectedaboveitissuggestedthatdespitealladvancesincosmeticschemistry,designinganeffective,stableandattractivecosmeticproductisstillachallengeformanufacturers.

Themostnotableissueisrelatedtothelackofchemicalstabilityofactiveingredientsincosmeceuticals.Forexample,VitaminA,VitaminCandessentialoilsarealleasilydegradedovertimeevenwhenproperlystoredintightlyclosedcontainers.Anumberofstudiessuggestthatovertime,activeingredientsdecomposeby50%orevenmore.Theavailablescientificdataprovidesevidencethatproductshelflifeinamixedformshouldbeasminimalaspossibleotherwiseingredientspotencyislostduetotheirdecomposition.

Chemicaldegradationisacomplexprocessandofteninducesachainofunpredictablechemicalreactions.Withtime,itisalmostimpossibletodeterminealloftheproducedchemicals.Todate,noresearchdescribinghowallingredientsreacttotimealongsidetheirdegradationrateshasbeenconducted.Theingredients’behaviordependsonmanydifferentfactors.Scientificstudiesshowthatevenminorfactorssuchasviscosityandparticlesizeinemulsioninfluencedegradationprocesses.

Hydrolysisseemstobethemaincauseforthedestructionoftheactiveingredients.Thisisduetothebi-phasicnatureofthecream.O/worw/oemulsionsbothcontainwaterwhichharmsesterbondsofvitaminderivatives.

Unfortunately,itisverydifficulttocompletelyremoveoxygenfromtheemulsionasthereactivemoleculeiseasilydissolvedinwaterandoilyphases.Therefore,thoughatalowerrate,oxidationcanoccurincontainersthatwereneveropened.

Toincreaseproductshelflife,manufacturersdevelopedformsofvitaminAandEthataremorestabletohydrolysis.However,despitetheincreasedstability,suchformshavelowerbioavailabilitythusreducingtheirpotency.

Environmentalfactorsfurtherinfluencetheproductbeforeitreachestheconsumer.Storageandtransportationatelevatedtemperaturesandhumidityand/orexposuretolightisharmfulforcosmeticproductsasallacceleratechemicalreactionrates.Forsomeessentialoilsthereactionswereacceleratedby70-foldwhenexposedtotemperaturesof40-50degreesCelsius.Furthermore,nooxygenisrequiredtoinitiateautooxidationreactionsinessentialoils.Also,theirexposuretolightproducesveryreactivemoleculesthatdegradeotheringredients.

Anothersignificantconcernisthenumberofcosmeticproductrecalls.Assummarizedfromregulatorybodiesandindependentlaboratories,alargenumberofproductswasfoundtobecontaminatedbymicrobialbodies(ortheirproducts)orbyexcessiveamountsofpreservativesandtheirdegradationproducts.Minorcontaminationsinducefreeradicalreactions.

Someantioxidantsthataremeantasactiveingredientsfortreatmentcanactasstabilizersforotheringredientsduetoinhibitionofchemicaloxidationthatoccursintheformula.

Itbecomesapparentthatbythetimeconsumersreceivetheirproduct,itisalmostimpossibletopredictitschemicalstateandtheamountofactiveingredientspresent.

Ingredientsincompatibilityisnotverycommon,butcanoccurwhenherbalingredientsareused.Theytendtohavearichchemicalcomposition.AcommonincompatibilityfactorisrelatedtooptimalpHlevelsbetweeningredients.ThepHoftheskincreamisimportantforitsefficacy,andisoftenclosetoneutralvalue.TheloweracidicpHallowsforabetterproductconservation.LowerpHisalsobetterforthestabilityofVitaminA.pHchangesovertimeandbecomesanotherfactorthatinducesdecomposition.LongstoragetimecanalsoleadtothereleaseofNIAS(non-intentionallyaddedsubstances)whichintroducesadditionalchangestoproductformulationandmayincreasetheriskoftoxicity.

Itisalsosuggestedthatlongstoragetimeofhyaluronicacidoritsexposuretohydrolysisoroxidationmaysignificantlyaffecttheproductstructureandviscositywhichinturncanreduceitspotencyaswell.

So,tosummarizetheconclusions:

• Cosmeticproductsincludeanumberofveryunstableingredients.Thepotencyofacosmeticcreamissignificantlydecreasedduetodegradationofitsactiveingredientsovertime.Thelesstimethecreamisinamixedformpriortousagethemorepotentandlesstoxicitis.VitaminsA,Candessentialoilsaretheleaststableingredientsandwilldegradefirst.

• Chemicaldegradationisacomplexprocessproducinganumberofchemicals.Someofthemmaynotonlydecreaseproductpotencybutalsobetoxicorallergenic.Overtime,preservativesinacosmeticemulsioncanleadtosignificantmicrobialcontamination.

• Manufacturersshouldfindwaystoimprovetheirproducts,refrainingfromincreasedamountsofpreservatives.Longstorageinamixedformresultsinalongerinteractionperiodbetweenallingredientsthusinfluencingitschemicalstability.Productexpirationshouldbefromthedayitwasmixed(productiondate)ratherthanthedayitisopened.

• Regulatorsareprotectingconsumersfromunsafeproducts;however,theydonotaddressproductsthatlosequalityovertime.Consumersshouldbeawareofthechemicalinstabilityandunpredictabilityofcreamswhileinamixedformandhowtimeaffectsthem.

• Themostoptimalscenarioistouseacosmeticproductwithin2monthsafterbeingmixed.Ifproperstorageconditionsareapplied,productdegradation,decreaseinpotency,andincreaseintoxinswillbeminimized.

References

1. Manela-Azulay,M.,&Bagatin,E.(2009).Cosmeceuticalsvitamins.ClinicsinDermatology,27(5),469-474.doi:10.1016/j.clindermatol.2009.05.010

2. Hauri,U.(2013).Chemicalstabilityofcosmetics.Abstract_of_the_presentation_held_at_the_Swiss_Food_Science_Meeting_2013,__June_27-28,_2013,_Universitéde_Neuchâtel,__CurrentAndFutureFoodSafetyIssues:NotIntentionallyAddedSubstances(NIAS),47-52.Retrievedfromhttps://www.researchgate.net/publication/321128139_Chemical_stability_of_cosmetics

3. Mitsui,T.,ed.(1997).NewCosmeticScience,Chapter8:StabilityofCosmetics.191-198.ElsevierScience.doi:10.1016/b978-044482654-1/50010-7

4. Singh,V.K.SHELFLIFEOFTHECOSMETICSPRODUCTS|PharmaTutor.(2019).Retrieved8December2019,fromhttps://www.pharmatutor.org/articles/shelf-life-of-the-cosmetics-products

5. Naveed,S.,&Sajid,S.(2016).DegradationinPharmaceuticalCreams:AscorbicAcidDemonstratingPhenomenon:AReview.JournalOfBioequivalence&Bioavailability,08(02).doi:10.4172/jbb.1000272

6. Neza,E.,&Centini,M.(2016).MicrobiologicallyContaminatedandOver-PreservedCosmeticProductsAccordingRapex2008–2014.Cosmetics,3(1),3.doi:10.3390/cosmetics3010003

7. Scholtyssek,R.(2004).Protectionofcosmeticsandtoiletries.DirectoryOfMicrobicidesForTheProtectionOfMaterials,263-266.doi:10.1007/1-4020-2818-0_15

8. Budecka,A.(2014).Microbiologicalcontaminantsincosmetics–isolationandcharacterization.BiotechnologyAndFoodSciences,15-23.

9. Gamal,M.(2019).MicrobiologicalQualityAssessmentofSomeBrandsofCosmeticCreamsSoldWithinAlkhomsCity,Libya.JournalOfDentalAndMedicalSciences,14(2),60-65.Retrievedfromhttps://www.iosrjournals.org/iosr-jdms/papers/Vol14-issue2/Version-2/N014226065.pdf

10. Noor,R.,Zerin,N.,Das,K.K.,&Nitu,L.N.(2015).SafeusageofcosmeticsinBangladesh:aqualityperspectivebasedonmicrobiologicalattributes.JournalOfBiologicalResearch-Thessaloniki,22(1).doi:10.1186/s40709-015-0033-4

11. Aslam,S.,Rahman,S.,Sabir,Z.,&Maqbool,B.(2017).EVALUATIONOFCOSMETICSFORTHEIRPOTENTIALCONTAMINANTSANDDRUGRESISTANTMICROORGANISMS.ActaScientificaMalaysia,1(2),16-19.doi:10.26480/asm.02.2017.16.19

12. Guaratini,T.,Gianeti,M.,&Campos,P.(2006).StabilityofcosmeticformulationscontainingestersofVitaminsEandA:Chemicalandphysicalaspects.InternationalJournalOfPharmaceutics,327(1-2),12-16.doi:10.1016/j.ijpharm.2006.07.015

13. Špiclin,P.,Gašperlin,M.,&Kmetec,V.(2001).Stabilityofascorbylpalmitateintopicalmicroemulsions.InternationalJournalOfPharmaceutics,222(2),271-279.doi:10.1016/s0378-5173(01)00715-3

14. Sheraz,M.,Khan,M.,Ahmed,S.,Kazi,S.,Khattak,S.,&Ahmad,I.(2014).Factorsaffectingformulationcharacteristicsandstabilityofascorbicacidinwater-in-oilcreams.InternationalJournalOfCosmeticScience,36(5),494-504.doi:10.1111/ics.12152

15. Seagull,A.I.andMoyano,M.A.(2008).StabilityofvitaminCderivativesintopicalformulationscontaininglipoicacid,vitaminsAandE.InternationalJournalofCosmeticScience,30,453-458.

16. MaiaCampos,P.M.B.G.,Gianeti,M.D.,CamargoJr.,F.B.,&Gaspar,L.R.(2012).Applicationoftetra-isopalmitoylascorbicacidincosmeticformulations:Stabilitystudiesandinvivoefficacy.EuropeanJournalOfPharmaceuticsAndBiopharmaceutics,82(3),580-586.doi:10.1016/j.ejpb.2012.08.009

17. Gosenca,M.,Obreza,A.,Pečar,S.,&Gašperlin,M.(2010).ANewApproachforIncreasingAscorbylPalmitateStabilitybyAdditionofNon-irritantCo-antioxidant.AAPSPharmscitech,11(3),1485-1492.doi:10.1208/s12249-010-9507-8

18. Gianeti,M.,Gaspar,L.,BuenodeCamargoJúnior,F.,&BerardoGonçalvesMaiaCampos,P.(2012).BenefitsofCombinationsofVitaminA,CandEDerivativesintheStabilityofCosmeticFormulations.Molecules,17(2),2219-2230.doi:10.3390/molecules17022219

19. Carlotti,M.,Rossatto,V.,&Gallarate,M.(2002).VitaminAandvitaminApalmitatestabilityovertimeandunderUVAandUVBradiation.InternationalJournalOfPharmaceutics,240(1-2),85-94.doi:10.1016/s0378-5173(02)00128-x

20. Turek,C.,&Stintzing,F.(2013).StabilityofEssentialOils:AReview.ComprehensiveReviewsInFoodScienceAndFoodSafety,12(1),40-53.doi:10.1111/1541-4337.12006

21. Sarkic,A.,&Stappen,I.(2018).EssentialOilsandTheirSingleCompoundsinCosmetics—ACriticalReview.Cosmetics,5(1),11.doi:10.3390/cosmetics5010011

22. Apone,F.,Barbulova,A.,&Colucci,M.G.(2019).PlantandMicroalgaeDerivedPeptidesAreAdvantageouslyEmployedasBioactiveCompoundsinCosmetics.FrontiersInPlantScience,10,1-8.doi:10.3389/fpls.2019.00756

23. Secchi,G.(2008).Roleofproteinincosmetics.ClinicsInDermatology,26(4),321-325.doi:10.1016/j.clindermatol.2008.04.004

24. Böttger,R.,Hoffmann,R.,&Knappe,D.(2017).Differentialstabilityoftherapeuticpeptideswithdifferentproteolyticcleavagesitesinblood,plasmaandserum.PLOSONE,12(6),e0178943.doi:10.1371/journal.pone.0178943

25. Kogan,G.,Šoltés,L.,Stern,R.,Schiller,J.,&Mendichi,R.(2008).HyaluronicAcid:ItsFunctionandDegradationininvivoSystems.StudiesinNaturalProductsChemistryVol.34.Elsevier.BioactiveNaturalProducts(PartN),789-882.doi:10.1016/s1572-5995(08)80035-x

26. Olejnik,A.,Goscianska,J.,Zielinska,A.,&Nowak,I.(2015).Stabilitydeterminationoftheformulationscontaininghyaluronicacid.InternationalJournalOfCosmeticScience,37(4),401-407.doi:10.1111/ics.12210

27. Tokita,Y.,&Okamoto,A.(1995).Hydrolyticdegradationofhyaluronicacid.PolymerDegradationAndStability,48(2),269-273.doi:10.1016/0141-3910(95)00041-j

28. Chen,H.,Qin,J.,&Hu,Y.(2019).EfficientDegradationofHigh-Molecular-WeightHyaluronicAcidbyaCombinationofUltrasound,HydrogenPeroxide,andCopperIon.Molecules,24(3),617.doi:10.3390/molecules24030617

29. Bhope,S.G.,Nagore,D.H.,Kuber,V.V.,Gupta,P.K.,&Patil,M.J.(2011).Designanddevelopmentofastablepolyherbalformulationbasedontheresultsofcompatibilitystudies.PharmacognosyResearch,3(2),122.doi:10.4103/0974-8490.81960

30. Pellizzoni,M.,Molinari,G.P.,Lucini,L.(2011)StabilityofthemainAloefractionsandAloe-basedcommercialproductsunderdifferentstorageconditions.Agrochimica,LV(5),288-296.

Abouttheauthors:

AlexVasilkevich,MSc,ChemicalEngineering.ChemicalresearcherattheInstituteofBioorganicChemistry.LeadsresearchanddevelopmentforpharmaceuticalcompaniesinEuropeandCentralAsia.

JamesJ.Kowalczyk,PhD,OrganicChemistry.PhDdegreefromMIT,NIHPostdoctoralFellowatUniversityofUtah.20+yearsasamedicinalchemistinthepharmaceuticalindustry,3yearsasanorganicchemistsupportingthepharmaceuticalandbiotechindustries,and2yearsasabioanalyticalchemistatacontractresearchorganization.