]. Soc.Cosmet.Chem.

,25, 99-114 (February3, 1972)

Clear Zinc PyrithionePreparations

TERRY GERSTEIN, M.S.*

PresentedMay 24, 1971,Seminar,Washington,D.C.

Synopsis--ZINC PYRITHIONE, also kn,own as zinc pyridine-2-thiol-l-oxide, has been es-

tablished as an effective ANTISEBORRHEIC AGENT. Because of its limited aqueous
solubility it is currently being marketedas a suspensionin hair-cleansingand hair-grooming
preparations.A methodhasbeendevelopedin which clear,aqueous(aswell as nonaqueous)
productscan be prepared. The method is based upon the COMPLEXATION of zinc
pyrithione with certain ORGANIC AMINES. It appears that zinc pyrithione is highly
solublein many primary aliphaticamines. In other more complexamines,suchas the poly-
alkylenimines,a definitestablemolecularcomplexis formed. The ability of suchaminesto
complexand producea solubleform of zinc pyrithione is discussed
with respectto the
physicaland d•emical propertiesof the ensuingsolutions.
Basedon thesefindings,
CLEARHAIR Pi•EPARATIONScontaining
zincpyrithionecan
be preparedfor useas antidandruffcleansers,
rinses,groomingagents,and conditioners. Ex-
amplesare offeredof productformulationshavinglevelsof zinc pyrithionerangingfrom 700
to 20,000ppm (2%). Analyticaldata concerning
complexformationaswell as the complexes'
toxicologyare presented.

INTRODUCTION

Zinc pyrithione, also known as zinc pyridine-2-thiol-l-oxide

(ZPTO), has been establishedas an effectiveantiseborrheicagent (1).
It is currentlymarketedin shampooand hair dressings at concentration
levelsof about 0.5% in ,thehair dressingto about 1•o in the shampoo.
This active ingredient is presentin the form of a dispersedsolid in
theseproductssinceits solubilityis quite limited in bothwaterand oil
media. The literature statesthat its solubility in water is 10-20 ppm
at pH 7 and increases to 35-50 ppm at pH 8 (2). In ethanol,the solu-
bility is 290 ppm; in acetone,700 ppm; in benzene,3-5 ppm; and in
diethylether,0 ppm. In other solvents,the solubility increases--for
* Revlon ResearchCenter,Inc., 945 ZeregaAve., Bronx, N.Y. 10473.
99
100 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

example,in chloroform,,to0.34% and in dimethylformamide,to 0.81%.

The solubility in dimethylsulfoxideis reported to be 5.13% (2). Ac-
cordingly,it has been difficult to formulate suitable cosmeticcomposi-
tions containing solubilized ZPTO. Although the sodium salt of
pyrithione is highly solublein water, and like ZPTO has been found to
have fungicidal and bactericidalproperties,it, unlike ZPTO, has been
found toxic and unacceptablefor use in cosmeticsor dermatological
compositions for topicalapplicationto the skin (3).
HYPOTHESES

It was postulatedthat the solubility of ZPTO would be increased

in solventscontainingamino functionalgroups. The reasoningfor this
is basedupon the ability of certainheavymetalssuchascadmium,zinc,
copper,and nickel to form amminecomplexes.Zinc hasa coordination
number of 4 which meansthat it can attach itself spatiallyto 4 ligand
linkagesbesidesmaintaining its two primary valencelinkages. In the
molecularstructureof ZPTO (Fig. 1), two of the four availablespatial
positionsare filled by the oxygenin the oxide functionalgroupsof the
molecule. A chelateis formed. By selectingthe proper amine solvent
it washopedthat the chelatestructurewould be modifiedto allow for
the accommodationof a molecular complex containing amino groups
that would utilize the remaining two Werner bonds.

Figure 1. Zinc pyrithione (zinc pyridine-2-thiol-l-oxide)(ZPTO)

One of the first materialsto be testedwas reagent grade 28% am-

monium hydroxide. It wasfound that ZPTO wassolublein it to the
orderof 1 or 270. Althoughthis in itselfwasnot considered significant,
it provedsomewhatinterestingwhen a 1% solutionof ZPTO in am-
moniumhydroxidewasusedto neutralizeaqueousCarbopol941.* A
cleargel resultedthat had a pH of 8 and contained100 ppm or 0.01%
ZPTO. When the pH of the gel systemwaslowered,it wasfound that
* B. IV. Goodrich & Co., Cleveland, Ohio.
 ZINC PYRITHIONE PREPARATIONS 101

the growthof small,fine crystalshad formedthroughoutthe media.

Thus,whatin effectwe wereableto do wasto preparea near-saturated,
saturated,or supersaturated solutionof ZPTO relativelyquickly and
withoutthe presence of an equilibratingsolid.
The mechanismby which ZPTO producesa therapeuticeffecton
seborrheicdermatitisis not understood. If one postulatesthat the
mechanism of the actionof ZPTO is throughepidermalpenetration,
then one must concludethat it is not the ZPTO particlesbut rather
the moleculesthemselves that penetratethe epidermis. One can then
reasonthat the useof a saturatedsolutionof ZPTO cangivecorrespond-
ing effectsas a suspension
of the solidin contactwith its supernatant
liquor. If a 1% suspension of ZPTO containsonly 0.01% (100 ppm)
availablematerialfor epidermalpenetration,then the remaining0.99%
dispersedsolid can be consideredunavailablefor penetrationinto the
skin. Hence, theoretically,the clear Carbopolgel that was prepared
containing0.01%solubilized ZPTO canbe justasefficienta preparation
in relievingseborrheicdermatitisas an opaquepreparationcontaining
99-foldmore ZPTO as suspended material. This statementis conjec-
,ture and no attempt has been made to determine its validity either
experimentallyor clinically at this time.
EXPERIMENTAL

The procedurefor determiningsolubility was rapid, but only ap-

proximate,sincethe ultimate end of the testingwasnot the elucidation
of solubility data, but the formulation of hair products. Thus, 1 g of
ZPTO was dissolvedinto 9 g of the amine in question with gentle
heating, if necessary.The easewith which the ZPTO was dissolvedwas
noted alongwith the quantity of residualinsolublesat room tempera-
ture. An estimationof the solubility of ZPTO in the amine was then
made. Besidesammonium hydroxide, the following commonlabora-
tory amineswere testedfor their solventeffecton ZPTO:
triisopropanolamine
triethanolamine

N-methyldiethanolamine
N N-dimethylaminoethanol
N-ethyldiethanolamine
N,N-diethylaminoethanol
These amineshaveseveralcharacteristics in common. All are tertiary
amines;they have difunctionality in the form of alkanol groupsthat
102 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

lowertheirbasicitythroughan inductanceeffect;theyareall verypoor

solventsforZPTO. Otheramines whichproved,tobepoorsolvents were
trilaurylamine,
ethoxylatedcocoamine-15
molesETO, andmorpholine.
It was found that the followingcompounds containingprimary
aminofunctionalgroupsmadeexcellentsolvents:
n-dodecylamine
1,3-diaminopropane
N-(3-aminopropyl)
1,3-propanediamine
N- (3-aminopropyl)N-methyl-
1,3-propanediamine
bis(2-aminoethyl)sulfide
All of theseamineswere capableof dissolvingover 10% ZPTO.
There were alsoa numberof oxyaminocompounds that showedvery
goodsolventproperties. These were:
ethanolamine
diglycolamine
3-methoxy-n-propyl
amine
3-(2-ethoxyethoxy)-n-propyl
amine
3-[2-(2-ethoxyethoxy)ethoxy]-n-propylamine
Diglycolamine,*or 2-hydroxy-2'-aminodiethylether,was singledout
for its unique solvent properties: it can dissolve42% ZPTO. Of
course, the fact that this amine itself was water soluble was also con-
sideredfavorable. In relation to the ethoxylatedpropylamines,it was
observedthat increasingthe ethoxylation function lowers their solvent
capacities. Thus, while 3-(2-ethoxyethoxy)-n-propylamine
was able to
dissolveover 10% of ZPTO, the solubilitycapacityof 3-[2-(2-ethoxy-
ethoxy)ethoxy]-n-propylamine wasapproximately8%.
A numberof primaryaminesthat were expectedto be goodsolvents
but failed to be were:

N,N-dimethyl-1,3-propanediamine
N-(3-aminopropyl)cyclohexylamine
bis(3-aminopropyl)piperazine
4-(3-aminopropyl)morpholine
ethylenediamine
cyclohexylamine

* JeffersonChemical Co., Houston, Tex.

 ZINC PYRITHIONE PREPARATIONS 103

DISCUSSION AND APPLICATION

The solubilityof ZPTO in organicaminesmay be lookedupon as

the interaction of a Lewis acid and a Lewis base in which the ZPTO,
actingasa Lewisacid,acceptsa pair of electronsfrom an amino group
thus forming a covalentbond. Zinc is a classa metal, that is, it is an
electropositive metal that formsits moststablecomplexeswith ligands
in which the donoratom is nitrogen,oxygen,or fluorine (4). The sta-
bili•tyof the resultingmetal complexis a functionof the nature of the
ligand. With classa metals, the greater the base strength of the
ligandthe greateris the tendencyto form stablecomplexes.However,
thiswasfound not to be the casein all instances.Accordingto dissocia-
tion constanttables,cyclohexylamine, with a pK• of 10.64, should be
equalto if not a better solventfor ZPTO than dodecylamine(pK• 10.62)
(5). It wasshownthat cyclohexylamine wasa considerably poorersol-
vent than dodecylamine. Ethanolamine,with a relatively low pK• of
9.50, wascapableof dissolvingZPTO to over 30%. The high solvency
of ethanolaminecan be explained through chelation. The formation
of a chelate structure usually lends itself to stabilizing the complex,
and the more extensivethe chelation, the more stablethe system. Fig-
ure 2 showsa possiblethree-dimensionalchelate structure of ethanol-
amine. Observethe formation of a 5-memberedchelatering and note
that the spatial arrangementof the coordinationbonds allows zinc to
be positionedin the center of a tetrahedral structure (6). However,
2-amino-2-methylpropanol, which can be thoughtof asa dimethyl deriv-
ative of ethanolamine,NHsC (CHa)sCHsOH, is an extremely poor sol-
vent. This is not surprisingif the steric hindranceof the two methyl

ETHANOLAMINE
Figure 2. ZPTO-ethanolamine complex
104 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

groupson the carbonatomalpha to the aminofunctionis takeninto ac-

count. Many of the solubility inconsistenciesin this study can be ex-
plained by steric hindrance. In general,large bulky ligandsform less
stablemetal complexesthan do analogoussmallerligands.
Although the most stablemetal chelatescontainingsaturatedligands
form 5-memberedchelate rings, saturated 6-memberedrings are fre-
quently encountered(7). Figure 3 showsthe 6-rnemberedring that
1,3-diaminopropane formswith ZPTO. It is a goodsolvent.
Figure 4 showsthe complexformedwhen ZPTO is dissolvedin
N-(3-aminopropyl)-diethanolamine.Observethat a zinc chelatestruc-
ture is formed with the tertiary amino nitrogen atom and an oxygen

Figure 3. ZPTO-1,3-diaminopropanecomplex

CH•C
H•0H
 ZINC PYRITHIONE PREPARATIONS 105

atom of one of the hydroxyl groups. It was concludedthat the pri-

mary amino nitrogenatom doesnot participatein forming the chelate
structure. The experimentalproof for this is that when the analogous
compound without hydroxyl groups, N,N-diethyl-l,3-propanediamine,
wastestedfor its solventcapacityon ZPTO, the solubility of ZPTO was
reducedfrom well over 10% at 20øG to lessthan 1%.

Diglycolamine
The superior solventpower of diglycolaminecould be ascribedto
the formation of a tetradentatechelatestructurewith ZPTO (Fig. 5).

•k•
•.,•
..• ......
• DIGLY

Figure 5. ZPTO-diglycolamine complex

Diglycolamine,which may be thoughtof asa derivativeof diethyl ether,

was chosenas the solubilizing agent for ZPTO in severalclear formula-
tions (Table I). These formulations are limited by the low water
concentrationsthat are required for clarity. Increasingthe concentra-
tion of the water causesthe disruption of the ZPTO-diglycolamine com-
plex permitting free ZPTO to be thrown out of solution. The proto-
type hair-settinglotion formulation that was prepared (Table I) con-
tains 0.2% ZPTO and is clear. When water is addedit becomescloudy
due to liberated ZPTO. The pH of a 1:1 mixture with water is 8.8.
The shampoopreparationshownin Table I has good foaming proper-
ties due partly to the high diethanolamidecontent. As expected,the
106 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

Table I

Product Formulations Basedupon the ZPTO-Diglycolamine Complex

Clear Hair-Setting Lotion

Sequence Ingredient Per Cent

1 PolyvinylpyrrolidoneK-30 2.0
1 Anhydrous ethanol 91.7
2 Perfume oil 0.1
fZPTO 0.2

3 }Diglycolamine 1.8

4 3.7% hydrochloricacid 4.2

Clear Shampoo
Sequence Ingredient Per Cent

1 70-30 lauric-myristic diethanolarnide 23.8

1 Isostearic acid 17.0
1 Propyleneglycol 42.2

fZPTO 1.7

2 }Diglycolamine 15.3

Hair Gel

Sequence Ingredient Per Cent

1 Eracol CD-18 a 10 0
1 Glycerine 10 0
1 Propyleneglycol 30 0
1 95% ethanol 25 0
J'CarboFol
940 0 6075

2 •Water 23
0.07
6925

JZeTO
3 }Diglycolamine 0.63

Witco Chemical Co., New York, N.Y.

additiono15 waterprecipitates
the ZPTO. A 1:1 mixture o15 thisshampoo
with waterhasa pH ot59.5.
The hair-groominggel 15ormulation (Table I), basedupon a poly-
propoxylatedtriol, incorporatesdiglycolamineas both a solubilizer15or
ZPTO and as a neutralizing agent 15orCarbopol resin. This digly-
colamineneutralizedgel contains700 ppm ZPTO and hasa pH of 7.5.
Figure 6 is a photographthat comparesthis gel with a simpleCarbopol
gel neutralizedwith a systemcontaining1% ZPTO dissolvedin 28%
ammonium hydroxide. This particular ammonium hydroxide-neu-
tralizedgel contains200 ppm ZPTO and is cloudyat pH 7.6. Actually,
the diglycolamine-neutralized gel was initially clear but a15terseveral
days,small,well-definedZPTO crystalswere observeddispersedwithin
it. It appearsthat the re15ractive
index o15thesecrystalsis closerto the
re15ractive
index o15the surrounding media than the re15ractive indices
 ZINC PYRITHIONE PREPARATIONS 107

".•.....•. - ße.!:
... : •dl..::
:.•
..

• .• .• .,

•::;';'."' 2-'-

... • .•:•
. . ..; :_:.:•::•.':
.........
......•.-••,..•:•-............
.:•:-..:-.
:•,:. ....,.j:;
.... ..

.:Z
:•. '
..... .:•
ß "',."'•'....•..:
,i.' '.•.;•
'
._.
:•. :,...
• '•;•
...... •. }.
..
•-
:'
• .• .&

.--.,-,•?.....::....
:::-;.::.;.
:. '.,¾i,..:.:.;.;:..•,
--:.:. -....:.:
..:-:;:---.?..:':-:;:..
,;% ........ : -;• -.•:.......
•,....
• •. .'1.... .. ......
.;;•.•'.•

Figure 6. The an:monium hydroxide-Carbopol gel (left) contains 200 ppm ZPTO and is
cloudy. The diglycolaminc-Carbopolgel (right) contains700 ppm ZPTO and appears clear,
due to an optical effect

of the crystalsand media in the ammonium hydroxide-Carbopol prepara-

tion, thusmaking thesecrystalsmore difficult to observe. These crystals
will grow in sizebut the preparationwill continue to appear clear. By
altering the refractive index of the media the crystalswill be more
visually pronouncedand may give an unusual sparkling effect to the
product. Neither the efficacynor the toxicologicalproperties of the
for•nulations outlined in Table I have been determined.

Polyethylenimine
As the search for other amino solventsprogressed,we became in-
volved with a group of amines that were decidedlydifferent in their
properties: the polyalkyleniminesand particularly the polyethylen-
imines. This group was especiallyattractive in that their higher mo-
lecular weight and bulky molecular structure made them relatively in-
vulnerable to subcutaneousabsorption, a particular liability of many
smaller organic amines(8). Polyethylenimineis made by the acid-cata-
lyzed polymerizationof aziridine (Fig. 7). The resultingcationic poly-
mer, dependingupon polymerizationconditions,can have a molecular
weight ashigh as 100,000and have as a compositiona constantratio of
25% primary amine to 50% secondary amine to 25% tertiary amine (9).
108 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

AZIRID•NE H

POLYETHYLENIMINE
(PEI)

œigure 7. Acid-catalyzedpolymerization oœaziridine to form polyethyleneimine

What made this material unusual as comparedto other amines which

had been testedwas the fact that water or alcoholwasactuallyrequired
in order to dissolve ZPTO. In effect, we were now able to make clear
preparationsof ZPTO that contained large quantities of water. Ini-
tially, it wasfound that 1 part ZPTO can be convenientlydissolvedin
water using 2 parts polyethylenimineof molecular weight 600 (PEI).
The resulting solution, basedupon a 20% ZPTO concentration,had a
pH of 10.6and couldbe diluted to infinity with water without causing
the precipitationof ZPTO. It waslater determinedthat 1 part ZPTO
can be so]ubilizedwith as little as 1.35 parts PEI. When the pH of an
aqueoussolutioncontaining270 ZPTO and 470 PEI was lowered by
the slowaddition of 3.7•o hydrochloricacid, a precipitateoccurredbe-
low a pH of 8.8. The precipitatewasidentifiedas ZPTO by infrared
spectroscopy and was shownto have the samespectraas the crystals
growingin the diglycolamine-Carbopol hair dressing.
In a studyof the structureof the complexit was shownthat the
ultravioletabsorptionspectrumof a dilute aqueoussolutionof ZPTO
shiftsto one similar to sodiumpyrithione when aqueousPEI is added
(10). Sincesodiumpyrithioneis an ionic saltand hasno coordinate
covalentmetallinkages,the indicationis ,thatthe chelatebondswithin
the ZPTO molecule are broken. From this inference, the solubilization
of ZPTO by aqueousPEI can be accountedfor by either of two ex-
 ZINC PYRITHIONE PREPARATIONS 109

Figure 8. Possiblestructures of solubilizc{ ZPTO in aqueous PEI

planarions. The first (Fig. 8,A) is that a complex is formed with PEI
that is analogousto the tetraammonia zinc complexes. For this to
happen the two coordinationlinkages that form the internal chelate
structureof ZPTO would have to open and allow the total of four co-
ordinationlinkagesof zinc to form with PEI. The secondexplanation
(Fig. 8,B) is that of a decompositionof ZPTO into a pyrithionesalt of
PEI and zinc which would be complexedin alkaline PEI media. It•
this is the case,then a solution of ZPTO in aqueousPEI may exhibit
toxic pharmacologicalproperties similar to sodium pyrithione and
thereforerender its usein cosmeticcompositionsunacceptable.
To determine the nature of the PEI-solubilized ZPTO, a series of
chromatographictechniqueswasemployedin which gel filtration studies
were prominent. Gel filtration, a form of column chromatography,
separatessubstancesby molecularweight. The higher the molecular
weight, the more rapidly the substanceis eluted from the column.
ZPTO has a molecularweight of 318 comparedto approximately600
for the PEI which we used. If the two are not complexedthey should
separateon the columninto two peaks. It wasfoundthat PEI, zinc,and
pyrithionemigrateas one peak. This phenomenon
indicatesthat the
zinc and the pyrithione exist in chemicalcombinationin the PEI sys-
tem. This conclusion was also sustained from data obtained from thin-
layerchromatography
studies.
110 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

Extensive toxicological studies confirm the existenceof an intact

ZPTO molecule. A subacutepercutaneous toxicitystudyon the intact
skinof white albinorabbitswasperformedwith a 2% solubilizedZPTO
solution,pH 8.8. This 90-daystudyshowedthat ,therewere no demon-
strablesystemiceffectsproducedby the repeatedapplicationof the prod-
uct on skin at greatly exaggeratedlevels of intended human use (11).
Correspondingtestswith equivalentlevelsof sodiumpyrithionedid pro-
ducesystemictoxicity.
One of the first formulations prepared containing the ZPTO-PEI
complexwas a clear liquid hair dressingwith a ZPTO concentrationof
0.5% (Table II). This formulation was based upon an alkoxylated
liquid having hydrophylic-hydrophobicgroupings. Included in the
formulation were natural and synthetic esters,ethoxylated glycerine,
and other ingredientsthat we thought would contribute to a balanced
hair dressing. The total nonvolatile solidscontent was 20%. It was
decidedto determineclinicallyif the ZPTO-PEI complexin this product
basewasan effectivetreatment for seborrheicdermatitis. Before doing
this, the preparationwassubmittedto a seriesof pharmacological and
toxicologicaltests to which new products are subjectedin order to
maintain maximum consumersafety. After the safetyof the prepara-
tion had been establishedit was then offered for clinical testing in
Europe. Testswere conductedconcurrentlyby dermatologists in Great
Britain, France, and Italy. The resultsof all thesetestsindicated that
the preparationwasdefinitelyeffectivein alleviatingdandruffand, in
manyinstances,in controllingeventhemostseverecases(12).
Table II

Clear Liquid Hair Dressing

Sequence Ingredient Per Cent

95% ethanol 71. 697
Ucon fluid mixture a 13.5
Castor oil 2.0
Diisopropyl adipate 0.5
Liponic EG-I• 2.0
UV light absorber 0.05
Perfume oil 0. 313
Water 7.0

'ZPTO
PEI
(Water
0.5
1.0
1.0
3.7% hydrochloricacid 0.44 (q.s.--pH 8.9)
Union Carbide Chemical Co., New York, N.Y.
Lipo ChemicalsInc., New York, N.Y.
 ZINC PYRITHIONE PREPARATIONS 111

Table III

Product FormulationsBasedupon the ZPTO-PEI Complex

Clear Shampoo
Sequence Ingredient Per Cent
1 Sandopan DTC Acid• 20.0
1 Lauric alkanolamide 3.0
1 Water 67.0

ZPTO 2.0
4.0
PEI
Water 4.0

Clear Protein Hair Conditioner

Sequence Ingredient Per Cent
1 Water-soluble protein 1.0
1 Water 97.9

ZPTO 0.2
0.4
PEI
Water 0.4

Perfume-hydrotrope 0.1
3.7% hydrochloricacid q.s.--pH 8.8
Hair-Thickening Lotion
Sequence Ingredient Per Cent
1 PolyvinylpyrrolidoneK-30 7.0
1 Water 40.5
'ZPTO 0.5
PEI 1.0
Water 1.0
'Methocelresin
b 1.0

•Water 49.0
3.7% hydrochloricacid q.s.--pH 8.8
SandozChemical Industries,Hanover, N.J.
Dow Chemical Co., Midland, Mich.

A seriesof prototypeformulations
of otherhair products
waspre-
pared(Table III). In manycases the concentration
levelsof ZPTO are
unrealistically
high in orderto demonstratethe easeof incorporatinga
largequantityof the complex.The clearshampoo formulationshown
in Table III containsSandopan DTC Acid which is an ethoxylated
fatty alcoholmaterialhaving,in addition,a carboxylicacid function.
This acid surfactant is used to neutralize some of the excess PEI that
is availablewhen the ZPTO-PEI complexis formed. The pH of the
shampoo may be aslow as8.8 withoutaffectingclarity. This shampoo
exhibitsgoodfoamingproperties.
In placeof the SandopanDTC Acid other acidicsurfactants may be
used,suchasthe phosphoric acidestersof ethoxylatedfatty alcoholsor
112 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

the succinicacid half-estersof fatty amides. The use of ingredients

containingsodium ion shouldbe avoided becauseof the possibilityof
hydrolizingthe ZPTO at high pH's and forming the sodiumpyrithione
in situ.

Other prototypehair preparationsmade (Table III) were a collagen-

derived protein conditioner containing 0.2% solubilizedZPTO and a
clear hair-thickening lotion basedupon polyvinylpyrollidone that con-
tained 0.5% solubilizedZPTO. Both of thesepreparationshad a pH of
8.8.

Related Amines Tested

Besidesthe polyethylenimine,molecular weight 600, used in the

previousformulations,it was found that polyethyleniminesof higher
molecularweightsare alsosuitable. Polyethylenimines,for example,of
molecular weights of 1,200, 1,800, and 60,000 were able to solubilize
ZPTO in water. When the polyethyleniminefunction is ethoxylatedor
propoxylated,thus reducingthe primary amine content,the solubilizing
effecton ZPTO is reduced. If a modificationof the polyethylenimine
molecular structureis made so as to yield a linear polymericmolecule
composed of onlysecondaryaminefunctions,it hasno solubilizingeffect
on ZPTO.
It was found that when the molecular weight of polyethylenimine
is reduced to g00, ZPTO is readily dissolvedwithout the presenceof
water. Water can still be added to this solution without causingthe
precipitationof ZPTO. This wastrue of aminesof evenlowermolecu-
lar weight that may be consideredto be derivedfrom sectionsof the
polyethylenimine molecule. Thus, tris(2-aminoethyl)amine
and tetra-
ethylenepentamine (Fig. 9) showedsimilar behavior to polyethylen-

TRIS(2-AMINOETHYL)AMINE

TETRAETHYLENE PENTAMINE

Figure9. Formulasfor tris(2-aminoethyl)amine

and tetraethylene
pentamine
 ZINC PYRITHIONE PREPARATIONS 113

imine of molecularweight 300. It is interestingthat the building block

of these•nolecules,ethylenediamineitself,doesnot dissolveZPTO either
with or without water. This is not unusual when one realizes that
ethylenedia•nineis consideredthe weakestbaseamong the polymethyl-
enedia•nines,NH2(CH2)•NH2, due to its high inductive effect, its elec-
trostatic repulsion effect, and intra•nolecular hydrogen bonding that
should give the ethylenedia•nine•noleculea •nost stable 54ne•nbered
cyclicstructure(13).

CONCLUSION

It wasshownthat clear hair preparationscontainingZPTO can be

preparedby first complexingthe ZPTO in a varietyof organicamines.
Its solvation•nay be lookedupon as an acid-basereactionin which the
solubilityof the ZPTO is a function of the amine cmnplexant. Among
the factorsthat affectthis solubilityare the basestrengthof the amine,
its steric hindrance, the formation of chelate rings, and its inductance
and electrostaticeffects,all of which contribute to the stability or in-
stabilityof the complex. It is shownthat if the properprecautionsare
taken, safe and effectiveclear preparationscan be prepared. What
should be determined is the minionurn concentration of complexed
solubleZPTO in suchdear preparations that would be effectiveagainst
dandruff.

ACKNOWLEDGMENT

The author would like to acknowledgeand thank the following

individualswho have contributed to the findings: Dr. Earle W. Brauer,
Mr. ClydeM. Burnett,Mr. BernardL. Kabacoff,
andMr. Radhakrishna
B. Kasat.

(ReceivedMay 28, 1971)

REFERENCES

(1) Brauer,E. W., Opdyke,D. L., and Burnett,C. M., Antiseborrheic qualitiesof zinc
pyrithionein a creamvehicle,J. Invest.Dermatol.,47, 174(1966).
(2) ZincandSodium Compounds of Omadine, Tech.Bull.,OlinChemicals,NewYork,N.Y.
(g) Opdyke,D. L., and Burnett,C. M., Privatecommunication, RevlonResearch Center,
Aug. 25, 1965.
(4) Baslo,
F., andJohnson,
R., Coordination
Chemistry,
W. A. Benjamin,
Inc., NewYork,
1964, p. 126.
(5) Yukawa,Y., Handboobof OrganicStructuralAnalysis,
W. A. Benjamin,Inc., New
York, 1965,p. 584.
114 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

(6) Martell, A. E., and Calvin, M., Chemistryo[ the Metal Chelate Compounds,Prentice-
Hall, Inc., EnglewoodCliffs,N.J., 1959,p. 254.
(7) Irving, H., Williams, R. J. P., Ferrett, D. J., and Williams, A. E., The influence of ring
sizeupon the stability of metal chelates,J. Chem. Soc.,1954,p. 3494.
(8) Patty, F. A., Irish, D., and Fasset,D. W., Industrial Hygiene and Toxicology,Vol. II,
IntersciencePublishers,New York, 1963,p. 2037.
(9) PEI--The VersatilePolymer, Tech. Bull., The Dow ChemicalCo., Midland, Mich.
(10) Kabacoff,B. L., Intern. Rept., Revlon ResearchCenter.
(11) Burnett, C. M., Intern. Rept., Revlon ResearchCenter.
(12) Brauer, E. W., Intern. Rept., Revlon ResearchCenter.
(13) Gero, A., Inductive effect and hydrogen bonding as factors in the base strength of
polymethylenediamines, J. Amer. Chem.Soc.,76, 5159(1954).