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Stability of lactic acid and glycolic acid in aqueous systems

subjected to acid hydrolysis and thermal decomposition

Article · July 1997

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j. Soc.Cosmet.
Chem.,48, 165-174 (July/August)

Stabilityof lactic acid and glycolicacid in aqueous

systemssubjectedto acid hydrolysisand
thermal decomposition

MELGARDT M. D• VILLIERS, DALE ERIC WURSTER, and

KIRTI NARSAI, Research Institute
for IndustrialPharma•y,
PotchejStroom
University
for ChristianHigherEducation, PotchqStroom
2520, SouthAfrica(M.M.d.V., K.N.), andCollege ofPharmacy,
University
of Iowa,Iowa City, IA 52242 (D.E.W.).

Accepted
for publication
October
6, 1997.

Synopsis
Preformulationassessment of the compatibilityof the o•-hydroxyacids(AHAs) lactic acid and glycolicacid
usingdifferentialscanningcalorimetry(DSC)showeda numberof possibleincompatibilities.Changesin the
meltingbehaviorof 1:1 mixturesof lacticacidandglycolicacid,lacticacidand sorbicacid,and lacticacid
and methyl parabenwere observed.To exploretheseinteractions,the stability of aqueoussolutionswas
determinedat elevatedtemperatures. The kineticparametersdescribingdegradationweredeterminedfrom
HPLC or UV spectrophotometric analyses
of solutionscontaininglacticandglycolicacids.Only sorbicacid
and methyl parabendegradedwhencombinedwith either lacticacid or glycolicacid.Combinationwith
thesepreservativesis not of practicalimportance
sinceformulations
at low pH areusuallyself-preserving.
Other AHAs and commonlyusednon-ionicemulsionexcipientshad no influenceon the rate of either
glycolicacidor lacticaciddecomposition. Both lacticacidandglycolicacidwereextremelystableand not
subjectto thermal decomposition.

INTRODUCTION

Lacticacidandglycolicacidarefrom a groupof weakhygroscopic acids,which contain

an alcoholfunctionin the alphapositionrelativeto the carboxylgroup(1). This group
of acids,alsoknownasthe alphahydroxyacids(AHAs), arethe "star"ingredientsin the
new anti-aging, anti-wrinkle, and cell renewalproductsand are generallyincorporated
into formulationsat lessthan 10% w/w (2). Productsusedin beautysalonsmay contain
upto40% andproductsusedby physicians asskinpeelersmay containup to 70% w/w
AHAs. AHAs removethe outerlayersof the skin througha process knownaschemical
exfoliation(1). Although productscontainingAHAs are numerousin skin care tech-
nology,little informationis availableaboutthe physicochemical propertiesand stabill-
ties of the acids and their formulations (3).
165
166 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

The purposeof thisstudywasto determinethe compatibilityandstabilityof lacticacid

and glycolicacid in combinationwith otherimportantingredientsof emulsions. Pre-
formulation assessment
of the compatibility of severalAHAs with theseexcipients,
using1:1 mixturesand by analysisby differentialscanning
calorimetry(DSC)(4,5),
showedpossible
incompatibilities.
To furtherexploretheseinteractions,
the stabilityof
combinationsof lactic acid and glycolic acid and non-ionic emulsion excipientsin
aqueoussolutionswasdeterminedat elevatedtemperatures.

MATERIALS AND METHODS

MATERIALS

Lacticacid(88% aqueous solution),sodiumlactate(60% aqueous solution),glycolicacid

(98% powder),sorbicacid (99% powder),methyl paraben(99% powder),glyceryl
monostearate,cetylalcohol,isopropylmyristate,isopropylpalmitate,stearicacid,glyc-
erol, polyethyleneglycol 1000 monostearate,lanolin, and sorbitolwere suppliedby
eitherSigmaChemicals (St. Louis,MO), Saarchem (Krugersdorp,SouthAfrica),Croda
(North Humberside,UK) or BASF (Ludwigshafen,Germany).All solventsusedwere
analyticalor HPLC grade.Water for HPLC and oxygen-free
water wereused.

COMPATIBILITY EVALUATION BY DIFFERENTIAL SCANNING CALORIMETRY (DSC)

1:1 Mixturesof all possiblecombinations of lacticacid,glycolicacid,and the excipients

weremadeby grindingin an agatemortarandpestle200 mg of eachcomponent. The
mixturesweretransferred to 5-ml glassvials,closed,andleft forat least24 hoursto reach
equilibrium.Samples,5-10 mg, were weighedand hermeticallysealedin round-
bottomedaluminum DSC samplepans.Thesesampleswere then heatedat 10øC per
minute, from ambient to 300øC, in a nitrogen atmosphere(ShimadzuDSC50, Shi-
madzu,Kyoto,Japan).The instrumentwascalibratedusingan indium standardwith a
melting point of 156.4øC.

ACCELERATED STABILITY STUDIES

A seriesof kinetic runs was carriedout at 25, 40, 80, and 120øC. Ten percentw/w
solutionsof lactic acid and glycolicacid, alone and combinedwith excipients,were
preparedin water.To studythe effectof lacticacid concentration on the stabilityof
preservatives,solutionscontaining5, 10, and20% lacticacidandbufferedwith sodium
lactateat a pH of 3.83 (pKa of lacticacid)wereprepared.Solutions
werebubbledwith
oxygen-freenitrogenfor at leasttwo hoursto reducethe oxygenconcentration. Each
solutionwas filled in 10-ml amber ampoulesunder a nitrogenatmosphere, and the
ampouleswere then transferredto incubatorskept at 25, 40, 80, and 120øC. At
predetermined times,sampleswereremovedfrom the ovens,chilled,and storedon ice
for analysis.At leastduplicatesampleswereremoved.
 STABILTY OF LACTIC AND GLYCOLIC ACIDS 167

ANALYSIS OF AHA's AND EXCIPIENTS

Assays
for lacticacidandglycolicacidwereperformedusinga ShimadzuLC-6A system
with a C-3RA integrator(Shimadzu,Kyoto,Japan).The UV detectorwassetat 214 nm.
A modifiedmethoddescribed by ChengandGabbe(6) employinga 25 x 3.9-mm I.D.,
C•8 column(Micro Bondapack, 5pm, Waters,USA) and a mobilephasecomposed of
water:acetonitrile
(60:40v/v) containing3 mM ammoniumdihydrogen phosphate was
used.For the analysis
of methylparabenthe samechromatograph andcolumnwereused.
The mobilephasewaswater:acetronitrile (62:38 v/v). The wavelengthof detectionwas
254 nm. Samples weredilutedwith the mobilephase.
ForbothHPLCanalyses
a flowrateof 1 ml/min-• wasused,and20-plsamples
were
injectedontothe column.Peakareaswereusedto quantifylacticacid,glycolicacid,and
methylparaben.Calibrationdata for the analysismethodsare listed in Table I.
Sorbicacidin aqueous solutionhasa strongabsorptionmaximumat 258 nm dueto the
conjugated double-bond carbonylsystem.During storagethe intensityof thismaximum
decreasesconsiderablyanda new,veryweak,absorption maximumappears between215
and 225 nm (7). Degradationof sorbicacid in aqueoussolutionwas followed by
measuringchanges in absorbency at 258 nm usinga ShimadzuUV 2101 PC spectro-
photometer(Shimadzu,Kyoto, Japan), and the concentrationof unreactedacid was
calculatedfrom the absorbencyvalues.Calibrationdata are listed in Table I.

CALCULATIONS AND STATISTICAL ANALYSIS

The kinetic parametersdescribingthe degradationof the acidsand excipientswere

determinedby combinationof the resultsfrom the appropriateanalyticalmethods.By
following the changein concentrationas a function of time, the reaction order for
degradationwas estimatedand usedto calculatereactionrate constants,half lives, and
shelflives.Data at differenttemperatures
wereusedto estimateactivationenergiesfor
degradation.Activationenergies,pH values,and half-life valueswere comparedstatis-
tically at a 95% confidencelevel using the Student'st-test (Minitab, Minitab Inc.,
Pennsylvania,USA).

Table I
CalibrationData for HPLC or UV Spectrophotometric
Analysisof AHAs, Methyl Paraben,and
Sorbic Acid

Standard Standard Correlation

Concentration error of error of coefficient
Compound (mg/ml-•) Slope slope Y-intercept Y-intercept (r)
Lactic acid 0.05-0.10 17039 231 453 14 0.9998
0.20-1.00 28907 976 468 43 0.9996
Glycolic acid 0.20-1.00 22718 332 961 82 0.9999
Methyl paraben 0.03-0.15 11471 242 -431 11 0.9996
0.10-1.00 25996 768 -884 48 0.9999
Sorbic acid* 0.10-0.40 12.699 0.678 -0.0176 0.0008 0.9998

* UV spectrophotometric
analysis.
168 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

RESULTS

DSC COMPATIBILITY OF AHAs AND AHAs AND EXCIPIENTS

Interactions,as seenby DSC, were classifiedaccordingto changesin the thermograms

of mixtures,comparedto that of individual compounds.It is important to note that
these changesdo not occur in isolation; rather, two or more of them occur simulta-
neously,with the mostprominentoccurence beingusedto definea particularresult(8).
OverallDSC resultsshowedthat the AHAs werecompatiblewith mostof the excipients.
Only a mixture of lactic acid and glycolic acid (Figure 1) causedthe melting point of
glycolicacid at 79øC to disappear.New melting endothermsthen appearedat 200 and
260øC. This indicateda possiblereactionbecause both the methyl parabenand lactic
acid melting peaksdisappeared. Furthermore,in the melting thermogramof a mixture
of glycolicacid and methyl parabenor sorbicacid(Figure2), the melting pointsof the
methyl paraben,126øC,and sorbicacid, 135øC,respectively, disappeared.When lactic
acid and methyl parabenwere mixed, extra peaksappearedat 260øC, and when lactic
acidand sorbicacidwerecombinedthe sorbicacidmelting peakdisappeared anda new
endothermat 179øC appeared.

DETERMINATION OF RATE CONSTANTS AND KINETIC PARAMETERS

The initial solutionconcentrations

of lactic acid and glycolic acid were selectedfor the
kinetic studieson the basisof maximum concentrations usedin skin careproducts(1).
The solutionsused were 10% lactic or 10% glycolic acid solutions,and lactic acid

Endothermic

Glycolic acid

Lactic acid

Glycolic
I} ic acid + Lactic
Lact acid

! ! i i i

50 75 100 125 150 175 200 225

Temperature (øC)
Figure 1. DSC thermogramsof lactic acid, glycolicacid, and a 1:1 w/w mixture of the two.
 STABILTY OF LACTIC AND GLYCOLIC ACIDS 169

Endothermic

Methyl paraben

ß .

Sorbic acid

i i i I i i

50 75 100 125 150 175 200 225

Temperature (øC)
Figure 2. DSC thermograms
of methyl paraben,sorbicacid, and 1'1 w/w mixturesof glycolicacid and
thesepreservatives.

solutionbufferedat pH 3.8 with sodiumlactate.The kinetic parametersdescribing

decomposition were determinedfrom appropriateanalysisresultsobtainedfrom cali-
bratedmethods.Calibrationdata for analyticalmethodsare listed in Table I.
For all the analysismethodsused,the resolutionvalues(Rs) betweenthe compounds
and their main degradationproductswere greaterthan 1.3, and calibrationgraphs
(TableI) showedexcellentlinearityin the concentration
rangesof interest.The precision
of the HPLC and UV methodswere obtainedby repetitivedeterminations(n -- 5) of
standardsolutions,and the relative standarddeviationswere found to be 1.3 + 0.3%.
The relativestandarddeviationsfor paralleldegradedsamples(n = 5) variedby 1.5 +
O.4%.

The kineticsof degradationwere investigatedat elevatedtemperatures(Figure 3) since

the decomposition
ratesof lacticacid,glycolicacid, methyl paraben,and sorbicacid
at roomtemperature(25øC,TablesII, III) weretoo slowto obtainkinetic datawithin
a reasonabletime. At the conditionsstudied, the decompositionsof thesecompounds
followed apparent first-order kinetics becausethe mean correlation coefficient for
all calculationswas above 0.980. The apparent first-order reaction rate constants
weredeterminedfrom the slopesof the linesobtainedby plotting the naturallogarithm
of the residualconcentrationversustime (Figure 4). Becausethe reactionmechanisms
remainedunaltered,the predictedrate constantswere used to calculateshelf lives at
25øC. Predictedshelflivesand real time stabilitydataat 25øC arelistedin TablesII and
III.
170 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

11o

lOO
'• 90

"- 8o

= 70
o
-•- Lactic acid
• 60
-•- Glycolic acid
5o
0 50 100 150 200

Time (days)
Figure 3. Meanpercentage decrease
in lacticacid(I) and glycolicacid(0) concentration
with time in
aqueoussolutions
kept at 80øC.Resultsarethe meanplusstandarddeviationof solutionscontainingthe
AHAs and AHA excipientmixtures.

STABILITY OF LACTIC ACID AND GLYCOLIC ACID

Both lactic acid and glycolic acid were very stable in aqueoussolution under the
conditionsstudied(Figure 3), and degradationwas not differentwhen combinedwith
the variousexcipientstested(levelof significance,
p > 0.05). The shelflivesdetermined
for lacticacid(TableII) rangedfrom a low of 79 years,whencombinedwith isopropyl
palmitate, to a high of 98 yearswhen combinedwith sorbicacid (Table II). Results
showedno appreciable influenceof the excipientson the decomposition of the acids.
Theseresultsare not consistentwith the DSC results.It wasfoundthat DSC frequently
givesfalsepositive,seldom-falsenegative,results(8).

STABILITY OF EXCIPIENTS COMBINED WITH LACTIC ACID OR GLYCOLIC ACID

Kinetic studiesshowedthat exceptfor methyl parabenand sorbicacid(TablesII, III) all

the excipientswere stablewhen combinedwith AHAs under the study conditions.
Methyl parabenand sorbic acid were unstablewhen combinedwith lactic acid or
glycolicacid. The activationenergiescalculatedfrom Arrheniusplots were 3.45 and
3.84kJ/mol
-• forthedecomposition
ofmethylparaben
in 10%glycolic
acidand10%
lactic acid solutions,respectively.
The respective
shelfliveswere88 and 164 days.The
 STABILTY OF LACTIC AND GLYCOLIC ACIDS 171

Table II
Stability Resultsfor LacticAcid and ExcipientsCombinedWith LacticAcid
Concentration left Shelf life
after 6 months at 25øC
Combination Stability of* pH at 25øC (%) (to.9 = years)

Glycolic acid LA 1.91 98.2 83

Methyl paraben LA 1.84 98.6 85
Methylparaben MP 1.84 46.7 0.5
Sorbic acid LA 1.87 99.2 98
Sorbic acid SA 1.87 53.5 0.5
Sodium lactate LA 3.83 98.4 96
Glycerylmonostearate LA 1.92 97.6 85
Cetyl alcohol LA 1.90 99.2 82
Stearic acid LA 1.89 98.5 84
Glycerol LA 1.87 97.4 84
Lanolin LA 1.94 96.3 82
Sorbitol LA 1.95 97.5 81
PEG 1000 monostearate LA 1.92 97.3 82
Isopropylmyristate LA 1.91 97.6 82
Isopropylpalmitate LA 1.90 99.3 79

* LA = lactic acid;MP = methyl paraben;GA = glycolicacid;SA = sorbicacid.

Table III
Stability Resultsfor GlycolicAcid and ExcipientsCombinedWith GlycolicAcid
Concentration left Shelf life
after 6 months at 25øC
Combination Stability of* pH at 25øC (%) (to.9 = years)
Lactic acid GA 1.88 97.7 70
Methylparaben GA 1.87 98.2 67
Methyl paraben MP 1.87 32.1 0.2
Sorbic acid GA 1.83 96.3 89
Sorbic acid SA 1.83 44.2 0.5
Glycerylmonostearate GA 1.92 99.6 89
Cetyl alcohol GA 1.94 95.2 82
Stearic acid GA 1.87 98.3 81
Glycerol GA 1.88 97.3 79
Lanolin GA 1.87 98.6 86
Sorbitol GA 1.84 95.4 87
PEG 1000 monostearate GA 1.92 96.3 84
Isopropylmyristate GA 1.90 98.7 90
Isopropylpalmitate GA 1.86 99.2 86
* LA = lactic acid;MP = methyl paraben;GA = glycolicacid;SA = sorbicacid.

equivalent
acitvation
energies
were13.2and14.9kJ/mol
-• forthedecomposition
of
sorbicacid. In the presenceof glycolicacid, sorbicacid decomposes
rapidly with a
predictedshelflife at 25øCof only 185 days,andwhensorbicacidwascombinedwith
lactic acid, the shelflife was 197 days.This is not of practicalimportancesincethese
preservatives arenot commonlyusedat suchlow pH, andat verylow pH mostemulsions
are self-preserving.
 joURNAL
OF
TliE
SOCIETY
OF
cosMETIC
CliEMISTS
-4.0

-4.5

-5.0

-6.0

-6.5

-7.00 400
800 1200 1600
TimeIhours)
Apparent
first-order
Figure
4.
solution
plots
of
the
decomposition
and
atpH1.87
of
methyl
40øCparaben
in
([])' at0%
80øC aqueous
(&)'
andglycoli
acid
120øC
([])'
EFFECT
OF
LACTIC
ACID
coNCENTRATION
ON
TIdE
STABILITY
OF
ExCIPIENTS the
The
effect
wasof
lactic
at
aacid
studied
pHconcentration
of
3.8
and (0.06-0-22
M)
on
the
decompos
temperatures
of
40,
80,
and
120øC'of
Toexcipi
mainta increase
in

solutions
at
aconstant
lactic
acid pli,
sodium
lactate
was
concentration
did
not
However,
the
added
to
increase
the the
lactic
acid.
degradation
of
the
decomposition
rate
for
methyl
An
most
lactic
acid
paraben orof
the
increased
linearly(r

ß .mm•t)al
excipients-
. with
... n•c
anincrease
entration
of
....¥'n
anlactic
acid
AlIA and
an
increase
atin
emuls*on
buffered
temperature
3.8kr,•
and......
ßconcentration
0.9962),•:•,•o
containing
ahigh of
%The
use
lactic
acid
is
not'
otmetny•
P•....n*
recomme
thepossible
DiscUSSION '
From
the
DSC
compatibility
eYaluation
interactions
actuallyitcould
predictednot
kineticbe
concluded
which
of
consequences
mostly
because
lactic
acid
was
m
solution-
Users
of
thermal
number
of analysis
other in
compatibility
testing
difficulties
in
its
generalwould
agree
that
there
are
application
(4,5,8).
When a
materi
bein
 STABILTY OF LACTIC AND GLYCOLIC ACIDS 173

4.0

2.0-

1.0-

=0 •'• ! !
0.00 0.05 0.10 0.15 0.20 0.25

Concentration (M)
Figure 5. Effect of lactic acid concentration
on the apparentfirst-orderrate constantof methyl paraben
decomposition
at pH 3.83 and40øC(I), 80øC('), and 120øC(O).

tested have almost identical melting points, it is difficult to distinquish the thermal
eventsattributed to eachcomponent.Interpretationsof DSC curvesare alsoimpossible
when one componentdissolvesin another. In thesestudies,dissolutionoccurredeither
in the melt of the lower melting glycolic acid (melting point equal to 79øC) or in the
lacticacidsolution.All this indicatedthat falsepositiveswerelikely whenDSC dataare
usedto predictpossibleincompatibilities.
Therefore,to substantiateinteractionsseenby DSC, the thermal stability of aqueous
solutionswasstudiedto determinethe kineticsof decomposition of variouscombina-
tionsof the compounds. Informationon the stabilityof AHAs is scarce,but lactic acid
andglycolicacidarereportedto be verystablein aqueous solution.This wasfoundtrue
becauseboth lactic acid and glycolic acid remainedstable (Figure 3), regardlessof
exposureto high temperature,for six months.Furthermore,combinationwith excipi-
ents, and exposingthese mixtures to high temperature, did not decreasethe AHA
stability.
Informationaboutthe stability of the other excipientsat low pH was alsonot readily
available. Results obtained from acceleratedthermal stability studies of AHAs and
excipientmixturesrevealedthat only methyl parabenand sorbicacid wereunstableat
174 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

pH lessthan 2. This correlatedwell with resultsobtainedby previousinvestigators

(9,10). Methyl parabenunderwentacid-catalyzed esterhydrolysisin aqueousformula-
tions,suchaso/w emulsions, yieldingp-hydroxybenzoicacidand methanol(9,10). In
aqueoussolution,sorbicacid undergoesauto-oxidation,forming aldehydesand other
carbonyl-containingcompounds (7). Both werestableat a slightlyhigherpH; in par-
ticular,methyl parabenat a pH of 3.8 wasvery stable,asseenin TablesII and III.

CONCLUSIONS

Combinationof AHAs with the excipientstestedhad no influenceon the rate of either

glycolic acid or lactic acid decomposition.Thesetwo AHAs were stable.Among the
excipientsstudied,sorbicacidandmethyl parabenwereproneto decomposition when
combinedwith either10% lacticacidor 10% glycolicacidin aqueous solutions
at a pH
below2. This resultis not importantbecausethesepreservatives
arenot commonlyused
in productsat sucha low pH. When lacticacidwasbufferedat a slightlyhigherpH of
3.8, a markedimprovementin the stabilityof methylparabenwasobserved.An increase
in lacticacidconcentration
from 5 to 20% at pH 3.8 led to an increasein decomposition,
but decomposition wasstill slowerthan at pH lessthan 2.

REFERENCES

(1) R. W. Siegfried,Formulatingwith alphahydroxyacids,Drug Cosmet.

Ind., 156(6), 30-37, 104-105
(1995).
(2) B. Idson,Treatmentcosmetics II. Retinoidsand AHAs, Drug Cosmet. Ind., 156(5), 24-28 (1995).
(3) Stateof the industry,Drug Cosmet.
Ind., 156(6), 28-35, 43-44 (1995).
(4) A. Smith, Use of thermalanalysisin predictingdrug-excipientinteractions, Anal. Proc.559-561,
(December 1982).
(5) M.J. Hardy, Drug-excipientcompatibilitypredictionby DSC, Anal. Proc.,556-557 (December
1982).
(6) H. Chengand R. R. Gabbe,Stability-indicating high-performanceliquid chromatographicassayfor
lacticacidin lotions,J. Chrom.,335, 399-406 (1986).
(7) S.S. Arya, Stabilityof sorbicacidin aqueous
solutions,J.Agric.Food.Chem.,28, 1246-1249 (1980).
(8) A.A. Van Dooren, Design of drug-excipientinteractionstudies,Drug Dev. Ind. Pharm.,9, 43-55
(1983).
(9) K. A. Connors,
G. L. Amidon,andV. J. Stella,Chemical
StabilityofPharmaceuticals
(JohnWiley & Sons,
New York, 1986), pp. 580-586.
(10) N. N. Ravaland E. L. Parrott,Hydrolysisof methylparaben,
J. Pharm.Sci.,56(2), 274-275 (1967).

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