determinacion de preservativos en shampoo

8/2/2019 Determinacion de Preservativos en Shampoo

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j. Soc.Cosmet. hem.,38, 307-319 (September/October987)

Determinationf shampoo reservativetabilityandapparent ctivation nergies y the linearregressionmethodof preservative fficacy estingD. S. ORTH, C. M. LUTES, S. R. MILSTEIN, andJ. J. ALLINGER, TheAndrew ergensompany,535 SpringGroveAvenue,Cincinnati, OH 45214.ReceivedctoberO, 1986.

SynopsisPreservativefficacy estswereperformed n stability samples f a shampoo uring storage or 18 mo. at3, 20, 38, and 49C.The shampooreservativeystem eteriorated ith increasingtorageime andtemperature, s measured y the "linearregression ethod."Thus, the decimal eduction ime (D-value),whichwasusedas the measure f the rate of death or Escherichiaoli,Pseudomonaseruginosa,nd Bacillussp., increasedrom about4 hr to over30 hr afteracceleratedgingat 49C or 3 mo. The D-values or$taphylococcusureusncreasedmore slowly.Apparent ctivation nergiesEa') for the changen shampooreservativeotencywerecalculatedrom heD-values t different emperatures.he Ea' values ecreasedrom -7, -6, and -4 Kcal/mole t 1 mo.to -16, -10, and -9 Kcal/moleat 12 mo. for shampoo hallengedwith E. coli, P. aeruginosa,ndBacillus p., respectively. his lossof preservativeystem otency ppearedo follow irst-order r pseudofirst-order eaction inetics,while the magnitude f the Ea' variedwith the lengthof storage nd he testorganisms sed.This work llustrateshe need or usingdifferentmicroorganismshenconductingreservativefficacytests f cosmeticroductsndshows ow hequantitativealues btained y the inear egressionethodarewell-suitedo monitoring tability ests.The useof this method or determininghe apparentmolarconcentrationf a preservativerom D-values nd for predicting he stabilityof cosmetic reservativesystemsrom Ea' values s discussed.

INTRODUCTIONStability esting s the final step n the development f cosmetic roducts. he objectiveof this esting s to demonstratehata product oes ot change ignificantlyuring tsexpected helf ife. Product tability s necessaryecauseeveralmonthsor yearsmayelapse etweenhe time a cosmetics manufacturednd usedup by the consumer.Recognizinghis, currentGoodManufacturingracticescGMP) or humanOTC drugproducts tipulate hat productsmustbe stable or at least3 yr. and that this mustbesupported y appropriatetabilitydata 1). In many nstances,GMP areused sa basisforsupportingocumentationorcosmeticroducts.hus,stabilityestsmaybeper-

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308 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTSformedby storage f products t variousemperaturesor up to 5 yr. to demonstratesatisfactoryhelf ife.Microbialspoilagemay occur n aqueous roducts nd in anhydrous roductshat areexposedo water;consequently, osmetic reservativesre included n formulationsoinhibit the growth of bacteria,yeasts, nd moldswhile products re n tradechannelsand in the handsof the consumer. he principles f preservativefficacyestinghavebeen eviewed2,3), including he need or demonstratinghat products aveadequatestability 2).Althoughseveralmethods f preservativeestingare available4-6), our laboratoryuses he "linearregression ethod"becauset provides rapid, quantitative xpressionof the rate of death of specific est organismsn a product when using defined estconditions 4). The rate of death determinedby the linear regression ethod s ex-pressed s the decimal eduction ime (D-value), which is the time required or inacti-vation of 90% of the populationof test organisms.The rationale or usingD-values s that everyorganism asa characteristicate of deathwhen subjectedo a specificethal treatment 4). This enables laboratoryo providequantitative esultson the rate of inactivation f specific est organismsn a product.Thus, the linear regression ethodcanbe used o determine he effectof formulationchanges nd componentnteraction n the stabilityof the preservativeystem.Since he linearregression ethodwasadopted,we haveobserved hangesn preserva-tive efficacy f some ormulations uring the course f stabilitystudies.This reportillustrates he value of performingpreservativefficacy estson stability samples yshowinghow a shampoo reservativeystem eteriorates ith age.

EXPERIMENTALTEST ORGANISMS

The test organisms sed n thesestudieswere aken rom the Jergens ulturecollectionand consisted f StaphylococcusureusFDA 209 strain),PseudomonaseruginosaPRD 10strain),Bacillus p. (isolated rom a contaminatedosmetic roduct),andEscherichiaoli(ATCC 8739). These organismswere cultured and used for challenging he testsamples, s describedn a previous eport 4).TEST SAMPLES

The test samples onsistedf a proprietaryormulation f a shampoon high-densitypolyethyleneontainers.he shampooontainedmmoniumaurylsulfate, ocamido-propylbetaine, ropylenelycol,polysorbate0, hydrolyzednimal ollagen,etraso-dium EDTA (and other ngredients), nd waspreserved ith methylparabenMP],chloromethylisothiazolinoneCMIT], andmethylisothiazolinoneMIT].STABILITY TEST

One bottle of freshlyprepared hampoo asused or the initial determinationsi.e.,0-mo.). Several ottles f the testsamples erestored t refrigeratoremperature,oom


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SHAMPOO PRESERVATIVE TESTING 309

temperature, 00F,and 120F i.e., 3, 20, 38, and 49C, respectively)forhedurationof the stabilitystudy.One bottle of product tored t each emperature asremovedat specifiedimes and subjectedo preservativefficacy esting. After sam-pling, the bottleswereplaced n the sample torage rchives.TEST PROCEDURE

A 0.1-mL aliquotof test organism uspension,ontaining bout 108organisms/mL,wasadded o ca. 50=mLportionsof each est sample n 100=mLscrew-cappedottles.Aerobicplate countsweredetermined, nd D-valueswerecalculated sdescribedn anearlier eport 4).HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY (HPLC)

Test samples f shampoo erediluted o 1% (wt/vol) n mobilephase.After filtration,the sampleswere assayed y injecting250-1zLaliquotsonto a 250 x 4.6 mm i.d.LiChrosorb RP-18 (5 Izm) columnwith a 40 X 4.6 mm i.d. guard columncon-taining Perisorb RP-18, 30-40 Izm. Chromatographiconditions ereas follows:mobilephase= water:methanol45:55) with 0.2% acetic cid, low rate0.5 mL/min,temperature5C,anddetectorange .05 AUFS. The column ffluentwasmonitoredat a UV wavelength f 275 nm.CALCULATION OF APPARENT ACTIVATION ENERGY

The apparent ctivationnergyEa') for the shampooreservativeystem asdeter=mined or each estorganism t each ime periodof the stabilitystudy i.e., 1, 3, 6, or12 mo.). A plot of Log 2.303/D-valuevs 1/T (whereT is the absoluteemperaturenK) wascalculatedor each estorganism, ndthe slopeof each ine wasdetermined ylinearregression.he Ea' hasa valueof - 2.303R (slope),which s the samecalcula-tion as for Ea (17). Preservativefficacy estswere not performed n samples toredbeyond mo. at 49Cor 12 mo. at 38C.The D-values btained n samplestoredor18 mo. at 3 and 20C were not used in calculation of Ea' values becauseD-values atthe higher emperatures erenot available.RESULTSFigure ! shows he changesn preservativefficacyhat occurred uring storage f theshampoot 3, 20, 38, and49C or 18 mo. whenusingE. coliasthe challengeorganism. t is apparent hat the preservative ystemwas not stableand that the D-values ncreased ith increasing torageime and temperature. hus, the D-values orE. colichangedrom


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310 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTSlOO

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MONTHS ON STABIUTY TESTFigure 1. D-values or E. coli n shampoofterstorage t 3, 20, 3 , and49C or l, 3, 6, 12, and 18. 8o. Explanationf symbols:,__i,, shampootored t 49C;O--O, shampootored t 3 C; I--I,I--, shampootored t 20C; nd }--{, shampootored t 3C.obtainedwith E. coli;however, omparison f Figures1 and 2 revealshat the teststrainof E. coliwasslightlymore esistanto the preservativeystemhan he teststrainof P.aeruginosased n thesestudies.

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MONTHS ON STABILITY TEST8 oigure 2. D-valuesor P. aeruginosan shampoofterstoraget 3, 20, 3 , and49C or 1, 3, 6, 12, and18 mo. Explanationf symbols:,__i,, shampootored t 49C;O--, shampootored t 38C; --,shampootored t 20C;and [--I, shampootored t 3C.


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Figure3 illustrateshe stabilityprofileof the shampoo henchallenged ith Bacillussp. The D-valuesobtainedwith this gram-positivepore ormerat several oints ntime were similar to thoseobtainedwith P. aeruginosa.lthoughS. aureus asmuchless esistanto the preservativeystem han the other test organisms, torage f theshampoo ecreasedhe potency f the preservativeystemor this organism. hus, theD-values hangedromaround hr at the outsetof the stabilitystudy o 7.6 hr afterstorageor6 mo. at 49C nd o 9.8 hr afterstorageor 12 mo. at 38C Figure ).The preliminaryHPLC analysesor MP, CMIT, and MIT revealed hat the concentra-tion of MP was unchanged nd that the concentration f isothiazolinonesppeared ohavedecreasedn all shampooest sampleshat had beenused n the stabilitystudy. Ashampoo pikedwith MP, CMIT, and MIT and assayedy HPLC gave he chromato-gram shown n Figure5. Here, the CMIT and MIT peaks re clearlyevident.This maybe contrastedwith the chromatogram btained rom a shampoo ged for 18 mo. at38C Figure ), in whichno MIT peak s evident.Similar indingswereobtainedwithshampoo amples toredat the higher emperatures.The Ea' values or the changen the shampoo reservativeystemwerecalculated ysubstituting .303/D-values or the reaction ate constantsk) in the Arrheniusequa-tion (7). The results resentedn Table show hat the Ea' values or the shampoopreservativeystemncreasedegativelyrom - 7, - 6, and - 4 Kcal/mole t 1 mo. to- 16, - 10, and -9 Kcal/moleat 12 mo. whenperforming reservativefficacyestswith E. coli,P. aeruginosand Bacillus p., respectively.nsufficientdatawereavailablefor calculating changen Ea' values uring he first 6 mo. of the studywhen estingwith S. aureus ecausehis organismwas inactivated o quickly in the shampoo.The

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MONTHS ON STABILITY TEST8 Figure3. D-valuesorBacillusp. n shampoofterstoraget 3, 20, 3 , and49C or 1, 3, 6, 12, and18mo.Explanationfsymbols:--&, shampootoredt49C;O--O, shampootoredt 38C;--I,shampootored t 20C; nd }--{, shampootored t 3C.


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312 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTSlOO

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MONTHS ON STABILITY TESTFigure 4. D-valuesorS. aureusn shampoofterstoraget 3, 20, 38, and49C or 1, 3, 6, 12, and 18Cmo. Explanationf symbols: --&, shampootored t 49C;O--O, shampootored t 38 ; I--I,shampootored t 20C; nd }--{, shampootored t 3C.Ea' values obtained with S. aureus were calculated to be -2 and -4 Kcal/mole fromD-values btained fter he shampoo asstored or 6 and 12 mo. respectively.Regressionines or the plot of Ea' vsmonthsof storage erecalculatedor the testorganismsFigure7). The slopes f these egressionshowed similarprogressionor allof the testorganisms, xhibitingvalues f - 0.8, - 0.4, - 0.6, and - 0.3 Kcal/mole/month and the correspondingorrelation oefficientsr) of -1.00, -0.93, -0.75,and - 1.00 for E. coli,P. aeruginosa,acillus p., andS. aureus,espectively. hesedatasuggesthat the lossof preservativeystem otency n the shampooollowed irst-orderor pseudo irst-order eactionkinetics.

DISCUSSION

Acceleratedging, or storage t elevatedemperatures, asbeenused o study he shelflife of cosmetic roducts nd/or o determinehe effectof physical nd chemical aram-etersof the formulaon preservativetability 8,9). Severaleportsndicate hat cosmeticpreservativeystemsmay nteractwith componentsf the formulaor packagingmate-rials, with concomitantossof preservativeotency 9-14).In the present tudy, he preservativeystem f the shampoo as ound o be unstable,as indicatedby the change n D-valueswith time and temperature.Higher storagetemperatures roduced airly rapid deteriorationn shampoo reservation,s deter-minedwith E. coli,P. aeruginosa,ndBacillus p. This inactivation f the preservativesystemwas not as obviouswhen usingS. aureus s the challenge rganism Figure4)becausehe net antibacterialeffect of the shampoo discussed elow) inactivatedS.


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Figure 5. HPLC chromatogram f shampoo pikedwith methylparabenMP), chloromethylisothiazo-linone (CMIT), and methylisothiazolinoneMIT).

aureusapidly. The differencesn the ratesof inactivationof the preservative ystemoccurring t 3 to 49Cwerenot due o differencesn the shampooamples, ecausellsamples sedat each ime/temperatureeriodcame rom the samebottle.The shampootored t 49C oroveronemonthwas he east esistanto contaminationby E. coli, as evidenced y the largerD-valuesobtained n comparison ith thoseobserved hen using he othertest organisms. his may be due, in part, to limitedactivity of MP againstgram-negative rganisms2) and, in part, to the ability of coli-forms o grow n the presencef anionic urfactants.or example, .0 ! % sodiumaurylsulfate s used to increasehe selectivity or coliforms n enrichmentmedia such asLauryl TryproseBroth (16).These indingsshow hat differentmicroorganismso not respondmonotonicallyo thepreservativeystem n the shampoo. his is why it is essentialhat preservativefficacytesting be performedusing test organisms ith all of the physiological haracteristicsexpected o be a potentialproblem n the formula. As a minimum, gram-negativeorganisms ith diversemetabolic apabilities, uchasP. aeruginosa,representativefthe coliform group, such as E. coli, a gram-positivecoccus, uch as S. aureus, nd agram-positive, pore-formingod (i.e., Bacillus p.) shouldbe included n preservativetesting. Thesebacteria, n addition o selected easts nd/ormoldsnot discussedn the


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314 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

Figure 6. HPLC chromatogramf shampoofterstorage t 3C or 18 months.currentwork, providesufficiently iversemorphologicalnd physiologicalharacter-istics o give reasonablessurancehat the test resultsoffera good ndication f theresistancef theproducto contaminantshatcould omentocontact ith theproductduring production r while in the handsof the consumer.Other considerationsn theselection f test organisms avebeendiscussed2).It is known hat some osmeticawmaterials ffect reservativefficacy.n addition, tshouldbe recognizedhat the preservativeystem f a cosmetic roductmay nvolve

Table IChangen Apparent ctivation nergiesEa')of ShampoouringStability esting

Ea' (Kcal/mole)*Test Organism 0 mo 1 mo 3 mo 6 mo 12 moE. coli -** -7 -9 - 1! - 16P. aeruginosa - - 6 - 6 - 9 - 10Bacillus p. - - 4 - 3 - 10 - 9S. aureus .... 2 - 4* Calculatedy substitutionf 2.303/D-valueork in Arrheniusquationsee quation3}).** Calculation ot performed ue to lack of sufficient ata.


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o 1 2 3 4 5 6 7 9 lo 11 12 13 14MONTHS ON STABIUTY TEST

Figure 7. Change n apparent ctivation nergiesEa') for the shampoo reservativeystem uring thestabilitystudy, determined sing est organisms. xplanation f symbols:--I, E. coli;O--O, P.aeruginosa;--, Bacillusp.;and __,, S. aureus.more than chemicalswith known antimicrobialactivity. Factorssuch as pH, wateractivity, nutrientavailability,surfactant oncentration,equesteringgents,and otherinterferences ill determine he extent o whichpreservativection s manifestedn anygiven formulation.Thus, the preservative ystemof a product nvolvesboth specificpreservativehemicals nd the physicochemicalonstitution f the entire ormulation.The inhibition of bacterialgrowth in a shampoomay conceivably e due to more thanone mechanismi.e., surfactant estabilization f cell membranes, reservative ctionon cellular metabolism,sequestration f divalent metal ions by tetrasodiumEDTA,unavailabilityof nutrients,etc.). One would not expectorganisms ith differentmeta-bolic capabilitieso be inactivated t the same ate in any cosmetic roduct. In thecurrentstudy, t was ound hat the four test organismsesponded ifferently o the netantibacterialeffectof the shampoo.Although the goal of this investigationwas not to determine he causeof change npreservative fficacy, he HPLC results evealed he presence f all three preservativesinitially, but only MP wasunchanged fter one week of storage t room temperature(Figures and 6). This suggestshat CMIT and/orMIT reactedwith somecomponentin the formula--possiblyhydrolyzed nimal collagen,becausehese sothiazolinonesare known to react with amines (15).It is known hat the rateconstantsor chemical eactions re nfluenced y temperature,as epresentedy theArrheniusquation17)

k = Ae r'RTwhere k is the reaction ate constant,A is the pre-exponentialactor, Ea is the activa-tion energy,R is the gasconstant, nd T is the absoluteemperature. ifferentiating


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316 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTSequation1} withrespecto temperaturend ntegratingetweenimitsyields quation{2} (17):

log 2 EaT2 T,) {2}k 2.303R (TT 2)Stumbo 7) reportedhat the D-value = 2.303/k; consequently, = 2.303/D-value.Substituting 2.303/D-values for k enablesone to use an expressionhat relatesD-values, aandT, as n equation3}:

D-valueEaT - T) {3}log -value2.303RTT)The ratesof reactionsn biological ystems reaffected imilarlyby temperature, o hatthe rate of inactivation f a givenorganism n the presence f preservativehemicalsorother physicochemicalonditions hat are bacteriocidal)ncreases ith temperature.Since D-values becomesmaller as the rates of microbial inactivation increase, t wouldbe expectedhat the D-value or a given organismn a test samplewould decrease ithan increasen preservativefficacy est temperature--as long as he preservative ystemwasnot alteredby the assay onditions.The situation s different n the currentstudy since he shampoo reservative otencywasevaluated t constant onditions i.e., by performing ll preservative fficacy estsat room temperature) fter test samples ad beenstored or specifiedimes at differenttemperatures. he preservative ystemwas found to be unstablewhen testedby thelinear regression ethod.This decreasen preservativeotencywith time and tempera-ture of storage esulted n decreasesn the slopes f the survivor urves 4) and corre-sponding ncreasesn D-values or each est organism.Although he slopeof the Arrhenius ctivation nergyplot is negativewhenk increaseswith temperature, he decreasen ratesof bacterial nactivationwith temperatureob-served n this studygivesa positiveslope n the Arrheniusactivationenergyplot, as sillustrated or the dataobtainedwith the test samples tored or 12 mo. and challengedwith E. coli Figure8). The Ea calculatedrom hese esults renegative; onsequently,theyaredesignateda'.The Ea' values alculatedor shampoo reservativeotency uring he first 12 mo. ofthe stabilitystudyappearn Table . The progressiveecreasen Ea' for all testor-ganisms eflects he decreasen preservativeystem otency.Here, the rate of change fpreservative ystempotencywasgreatest or E. coli i.e., the organismmost resistant othe shampoopreservative ystem)and smallest or S. aureusthe test organism eastresistant o the preservative ystem).Although he negative a' values ppearo be contradictoryo conventionalystemsnwhich Ea is determined,one shouldnote that the parameter eing measured--preser-vative systempotency--decreased ith increasingemperature, s determinedby thekineticsof inactivationof the test organisms.In general, the rate of a chemical eaction,as expressedy k, is a functionof theconcentrationf the reactants.f the concentrationf a reactanti.e., preservative)schanged sa resultof storage t elevatedemperaturesor different imes,determiningD-valuesand using 2.303/D-valueenables ne to determine at different empera-tures. Thesek valuesmay be comparedwith k valuesobtained n systems f known


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Figure 8. Arrheniusctivation nergy lot of shampooreservativeystem otency eterminedsingE.colias the challenge rganismn preservativefficacyestson samples tored t 3, 38, and 49C or 12months.preservativemolar concentration, o that one may determine he molar concentration(or the apparentmolar concentration)f activepreservativen the formula after anygiven time and temperatureof storage.Calculations f this type may be useful insystemscontainingonly one preservative hemical. Obviously, calculationswill bequite complex n productscontainingmultiple surfactants nd preservative hemicalsbecausehe lossof preservativeotencymay followhigher-ordereaction inetics. t isbelieved hat determiningD-values nd Ea' valuesmay be useful n studying he ki-neticsof bacterialdeath, in determining he apparentmolar concentration f a preser-vative, and in monitoring the performance f cosmeticpreservative ystemsduringstability studies.In discussingcceleratedtability esting,PopeusedEa valuesof 10-20 Kcal/mole orpredictinggoodprobabilityof formulation tability,whichhe definedasone that de-gradedno more han 10.5% in 3 mo. at 45C 18). He noted hat formulationshatdegrade hroughsolvolysisaveEa valuesof 10-30 Kcal/mole nd that systems ithEa values f this magnitude howmarked ncreasesn reaction atesat elevatedempera-tures.The findings n thisstudy evealedhat the unstable hampooreservativeystemhadEa' values f - 2 to - 16 Kcal/mole,depending n the time periodof the determi-nation and the test organismused. It is believed that the differencebetween the Eavaluesproposed y Popeand the Ea' valuesobservedn this study includingbothabsolutemagnitudeand algebraicsign) may be due to 1) the differencen k for thesolvolysiseactions itedby Popeandcomplexationeactions, uchas hose nvolved nthe interaction f isothiazolinonesndamines15); and2) the way n whichEa andEa'were defined and derived.The shampoo reservativeystemwassatisfactory henexamined t the outsetof thesestudies i.e., at 0 mo.), but it deteriorated uring the aging study. Hence, the Ea'


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318 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTSvalues for the shampoodecreased ith time. By way of contrast,determinationofD-values nd Ea' values or the test organismsn a proprietaryotion preserved ithMP andQuaternium-15evealed ochangesn these aluesor testsamplestored t 3to 49C for the durationof the stabilitystudy. This indicated hat the preservativesystemof the lotion wasnot changingdetectably,as evaluated y the linear regressionmethod.These xamplesllustrate useful aveat:he Ea' values hould eviateittlefrom the initial, acceptable alues f a product s to havesatisfactoryhelf ife.Thesestudiesdemonstratehat the linear regression ethod s useful or quantitatingthe ratesof inactivationof bacteria noculated nto stability test samples nd illustratethe value of this method or monitoringpreservative fficacyof stability test samples.To our knowledge, his is the first reporton the useof a quantitativemethod, whichprovides ia the kineticsof bacterial eath,a method o monitorpreservativeotency tvarious imesduring stabilitystudies f cosmetic roducts.In most nstances, reservativefficacyestingdemonstrateshat the cosmetic reserva-tive systemnactivatesest organismsapidlyand that the D-values re positive.Thepreservativeystem s judged o be inadequatewhen D-valuesare greater han accep-tancecriteria 4) or when hey are negative.For example, he preservativeystem ailswhen test organisms row in the sample.The slopeof the survivorcurve s positivewhengrowthoccurs,whichmeans hat the D-value s negative.NegativeD-valuesarerarely, f ever,reportedn publishediteraturebecausehey ndicate reservativeystemfailure and the need for reformulation.Althoughnegative a' values ppear o be somewhatnomalous,nemust keep nmind that they represent decreasen potency f the preservativeystem hat occurs nstorage nd that the rate of preservativeeteriorations acceleratedy increasesntemperature. s noted bove, egative -values reobtained hen estorganismsrowin the estsamples.egative -valuesannot eusedn calculatinga' values ecauseone cannot ake the log of a negativenumber.This reportshowshat the linear egression ethodmay be used or predicting hestability nd heapparent olar oncentrationf a preservativeystemn additiono itsalready-documentedtility in determininghe cosmeticreservativefficacy. hus,examinationf thepreservativefficacyf a formula fterstoraget 49C or 1 to 3 mo.may indicate he systems unstable nd that reformulations necessary.t is recom-mendedhat formulation hemistsuantirate reservativeystem otency uringaccel-erated gingstudieso determinehe likelihood f preservativeystemailure.ACKNOWLEDGEMENTThe authors xpressheir appreciationo Mr. W. E. Dickman or his assistanceithstability testing of the samples.REFERENCES(1) U.S. Food& Drug Administration, uman and VeterinaryDrugs, CurrentGood ManufacturingPracticen Manufacture, rocessing,acking, r Holding,Fed.Register,3, 45014-45087 (1978).(2) D. S. Orth, Principles f preservativefficacyesting,Cosmet.oilet.,96(3), 43-52 (1981).


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(3)(4)(5)(6)

(7)(8)(9)

(10)(11)(12)(13)(14)(15)(16)(17)(18).

H. N. Bhargava nd A. Anaebonam, ssentialsf cosmetic reservation,oap osmet.hem. pecial-ties, 59(10), 39-41, 125 (1983).D. S. Orth, Linear egression ethod or rapiddeterminationf cosmeticreservativefficacy,. Soc.Cosmet. hem., 30, 321-332 (1979).Anon, Microbiologicalests, antimicrobial reservatives--effectiveness,nitedStates harmacopeiaXIX, United StatesPharmacopeialonvention,Rockford,MD, pp. 587-592 (1975).Preservation ubcommittee f the CTFA microbiological ommittee, A guideline or the determina-tion of adequacy f preservationf cosmeticsnd toiletry formulations, GA Cosmet.., 2, 20-23(1970).C. R. Stumbo,Thermobacteriologyn food rocessing,cademicPress,nc., New York, p. 59. (1965).I. Matsuura,Methods or the predictionof shelf ife, Cosmet.oilet., 96(1), 39-44 (1981).G. Jacobs, . M. Henry, andV. F. Cotty, The influence f pH, emulsifier, ndacceleratedginguponpreservativeequirementsf O/W emulsions,. Soc.Cosmet.hem., 6, 105-117 (1975).M. M. Rieger, Current aspects f cosmetic cience. . The inactivationof phenolicpreservativesnemulsions,Cosmet. oilet., 96(5), 39-43 (1981).S. Tanenbaum,Pseudomonadsn cosmetics,J.Soc.Cosmet. hem.,18, 797-807 (1967).R. Bhadauria nd D. G. Ahearn,Loss f effectivenessf preservativeystems f mascarasith age,Appl. Environ.Microbiol., 9, 665-667 (1980).T. J. McCarthy, Microbiological ontrolof cosmetic roducts,Cosmet.oilet., 95(8), 23-27 (1980).P. A. Berke, D.C. Steinberg, nd W. E. Rosen,GermabenI, a complete reservativeystemnclear iquid form, Cosmet.oilet., 97(11), 89-93 (1982).S. M. Henry and G. Jacobs,Cosmetic reservatives--1982update, Cosmet. oilet., 97(11), 31-52(1982).J. Cowls,AmericanWaterWorksAssoc., 0, 979 (1938), Cited in: DifcoManual. DehydratedultureMediaandReagentsor Microbiology,0th ed. Difco Laboratories, etroit, p. 499. (1984)F. Danielsand R. A. Alberty, Physical hemistry,rd ed. JohnWiley & Sons, nc., New York, p.342. (1967).D. G. Pope,Acceleratedtability esting or prediction f drugproduct tability,DrugCosmet.nd.,127(6), 48ff (1980).

determinacion de preservativos en shampoo

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