pasquali, sacco, bregni 2010 lipogeles
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Stability of Lipogels with Low Molecular Mass Gelatorsand Emollient Oils
Ricardo C. Pasquali, Natalia Sacco, and Carlos Bregni
Departamento de Tecnologa Farmaceutica, Facultad de Farmacia y Bioqumica, Universidad deBuenos Aires, Buenos Aires, Argentina
The influence of preparation methods on stability of lipogels was studied. The objectives of thisstudy were to evaluate the ability of different low molecular solid ingredients used as excipientsin pharmaceutical and cosmetical products to form lipogels with emollient liquids of differentpolarities as well as to evaluate the stability of the lipogels obtained and the spreading abilityof stable lipogels. The lipogels were prepared by heating the mix of oil and gelator a 100C withtwo different forms of cooling: slow cooling of the without stirring and quick cooling with stirring.The stability tests were one year of storage at room temperature, centrifugation and three monthsat 40C. None of the lipogels prepared with slow cooling and without stirring were stable inall stability tests. Eight of the formulations with quick cooling and stirring were stables in allstability tests: six with 12-hydroxystearic acid, one with hydrogenated castor oil, and one with
beeswax as gelators. The lipogels with 12-hydroxystearic acid as gelator do not spread on skinor form clusters that spread after pressing with the fingers. The two lipogels with castor oil havegood spreading ability on the skin.
Keywords Emolients, gelators, gels, lipogels, organogels
INTRODUCTION
Organogels are semisolids systems formed by a gelatorand an organic liquid. Organogels of lipophilic liquidsare denominated lipogels or oleogels. An organogel isusually prepared by warming a gelator in an organic liquiduntil the solid dissolves, and then cooling the solution(or sol) to bellow the transition temperature.[1] The gela-
tors aggregates are linked in complex, three dimensionalnetworks that immobilize the liquid.[2,3]
Organogels can be divided based on the nature ofthe gelator in polymeric and low molecular mass organicgelators. Polymers immobilize the organic solvent by form-ing a network of either cross-linked or entangled chains forchemical and physical gels, respectively.[3] Low molecularmass organic gelators posses a relative molecular massbelow 3000.[4] These gels are viscoelastic solidlike materials,possessing both the elastic properties of ideal solids and theviscous properties of newtonian liquids.[5]
Two different types of three-dimensional networks andviscoelastic materials can be obtained in organogel systems.
In the first, materials exhibiting a solidlike, viscoelastic,mechanical behavior and which are made of permanent
networks obtained through a sharp solution (or sol) togel phase transition at a specific temperature are stronggellike systems. Strong or solid matrix gels[3] with perma-nent solidlike networks in which the nodes are spatiallyextended (pseudo) crystalline microdomains. In the second,materials exhibiting a liquidlike viscoelastic behavior whichare made of transient networks are termed weak gellike
systems. Weak or fluid matrix gels[3]
with transient net-works exhibiting no elasticity over long periods of time,in which the nodes are entanglements or spatially limitedorganized microdomains.[1] The vast majority of low mol-ecular mass organic gelators assemble into solid networkswhen added to appropriate organic solvents.[3] Fluidmatrices are formed upon the incorporation of polar sol-vents to organic solutions of surfactants, which results inthe reorganisation of surfactant molecules into mono orbilayer cylindrical aggregates that immobilize the solvent.An extensively investigated biocompatible organogels indrug delivery are formed by sorbitan monostearate[2] andsorbitan monooleate[6] as gelators. Anhydrous gels were
obtained by dissolving low concentrations (110%) of thegelator in liquid alkanes, isopropyl myristate and variousvegetable oils at 60C. Subsequent cooling of the systemyielded white thermoreversible gels at room temperature. [3]
Realdon et al.[7] prepared lipogels of peanut oil gellifiedwith white beeswax, a mixture of partial glycerides andesters of long chain fatty acids, glyceryl monostearate, amixture of mono and diglycerides of palmitic and stearic
Received 2 December 2008; accepted 31 December 2008.Address correspondence to Ricardo C. Pasquali, Departa-
mento de Tecnologa Farmaceutica, Facultad de Farmacia yBioqumica, Universidad de Buenos Aires, Junn 956, 6 piso(1113) Buenos Aires, Argentina. E-mail: [email protected]
Journal of Dispersion Science and Technology, 31:482487, 2010
Copyright# Taylor & Francis Group, LLC
ISSN: 0193-2691 print=1532-2351 online
DOI: 10.1080/01932690903212263
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acids, and polysiloxane polyalkylene copolymer. The lipo-gels were gelled in two different conditions: cooling toroom temperature and cooling at 35C under continuousstirring and maintaining the preparations undisturbed atroom temperature. Realdon et al. noted that these differ-ences in processing conditions may change the consistencyand the rheological behavior of the lipogels. They attributethese differences to the shape and dimension of the crystal-lites of the solid fraction and their ordering in three-dimensional structure. In a posterior study, Realdon,Ragazzi, and Ragazzi[8] observed considerable differencesin rheological characteristics when prepared lipogels bygelling olive oil with mono and diglycerides at rest, understirring, and milled after gelling.
Almeida and Bahia[9] where evaluated the physical stab-ility of two lipogels (sweet almond oil gellified with sorbi-tan monostearate and liquid paraffin with cholesterol)using three different methodologies: at different tempera-tures (20C and 40C) over a 3-month period, an acceler-ated test performed where the temperature changed
between 4
C and 40
C every 24 hours during 7 days andrheological tests. In the remaining consulted bibliographythere is not mention about physical stability studies oflipogels.[2,68,1019]
The objectives of this study are: 1) to evaluate the abilityof different low molecular solid ingredients that are used asexcipients in pharmaceutical and cosmetical products toform lipogels with emollient liquids of different polarities;2) to evaluate the stability of the lipogels obtained.
MATERIALS AND METHODS
MaterialsIsopropyl myristate, decyl oleate (Cetiol V), octyldode-
canol (Eutanol G), glycerol monostearate (Cutina MD),ethylene glycol distearate (Cutina AGS), dicaprylyl carbon-ate (Cetiol CC), 2-propylheptyl caprylate (Cetiol Sensoft)and cetyl isononanoate (Cetiol SN) were provided byCognis. Hydrogenated castor oil and 12-hydroxystearicacid are from Castoroil (Argentina) and sorbitan mono-stearate (Span 60) was provided by Uniquema (Argentina).Beeswax, paraffin, and mineral oil meets the requierementsof Farmacopea Argentina VI.
MethodsComposition of Lipogels
Lipogels were composed by 9.00 g of oil and 1.00 g ofgelator. The oils were mineral oil, isopropyl myristate,decyl oleate, castor oil, octyldodecanol, dicaprylyl carbon-ate, and cetyl isononanoate and the gelators were paraffin,hydrogenated castor oil, glycerol monostearate, beeswax,ethylene glycol distearate, and 12-hydroxystearic acid.
Preparation of Lipogels
By Slow Cooling without Stirring. The ingredientswere weighted in 20 cm3 transparent glass vials with a plas-tic cap and warmed at 100 2C until total fusion of gela-tor. The warmed glasses were shaked for homogenize andthen cooling to room temperature on a heat insulating sur-face, at rest and without extra refrigeration (mean cooling
velocity before gelation approximately 5C=min). Twosamples of each formulation were prepared.
By Quick Cooling with Stirring. Lipogels were pre-pared in a same way that previous, except that the coolingwas performed by stirring with a magnetic bar of 12 mm inlength and refrigeration with a water bath at 25C (meancooling velocity before gelation approximately 40C=min). Two samples of each formulation were prepared.
Physical Stability
The vials were stored lying down 30 days at room tem-perature. It was observed gels formation and liquid separ-
ation. A lipogel is considerate unstable with a minimumseparation of liquid. A portion of the stable lipogels (1 g)was centrifuged (30 minutes at 2500 rpm). The remain ofthe stable lipogels were stored additional eleven monthsat room temperature and the duplicates three months at40 2C.
RESULTS AND DISCUSSIONS
The results of the stability tests are showing in Tables 1through 4.
Lipogels Prepared with Slow Coolingand without Stirring
Mineral oil, dicaprylyl carbonate, cetyl isononanoate,and 2-propylheptyl caprylate do not produce lipogels thatare stables after 30 days at room temperature.
Isopropyl myristate gelify without liquid separation with12-hydroxystearic acid. The lipogel is stable by centrifuga-tion and unstable after one year at room temperature andthree months at 40C.
Decyl oleate and octyldodecanol gelifyes without liquidseparation with ethylene glycol distearate. This lipogels areunstable by centrifugation and after one year at room tem-
perature and three months at 40C.Castor oil gelify without liquid separation with glycerol
monostearate, beeswax and ethylene glycol distearate. Thislipogels are stables by centrifugation. The lipogel withbeeswax is the only stable after one year at room tempera-ture and the three are unstable after three months at 40C.
Not one lipogels prepared with slow cooling and with-out stirring are stables in all stability tests.
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Lipogels Prepared with Quick Cooling and Stirring
Mineral oil, dicaprylyl carbonate, isopropyl myristateand cetyl isononanoate gelifyes without liquid separationonly with 12-hydroxystearic acid. The formed lipogels arestables in all stability tests.
2-Propylheptyl caprylate and decyl oleate gelifyeswithout liquid separation with hydrogenated castor oiland 12-hydroxystearic acid. The lipogels with 12-hydroxystearic acid are stables in all stability tests, but withhydrogenated castor oil are unstable by centrifugation.
TABLE 2Stability at centrifugation of lipogels that are stable after 30 days of storage at room temperature: G gel,
GL gel and liquid, unstable after 30 days of storage at room temperature; up: slow cooling without stirring;
down: quick cooling with stirring
Gelatoroil Paraffin
Glycerolmonostearate Beeswax
Ethylene glycoldistearate
12-Hydroxystearicacid
Hydrogenatedcastor oil
Sorbitanmonostearate
Mineral oil G
Dicaprylylcarbonate
G
Isopropyl myristate GG
Cetyl isononanoate G
2-Propylheptylcaprylate
G GL
Decyl oleate GL G GL
Castor oil G G G G G G G
Octyldodecanol GLG
TABLE 1Stability of lipogels after 30 days of storage at room temperature: G gel, GL gel and liquid; up: slow cooling
without stirring; down: quick cooling with stirring
Gelatoroil Paraffin
Glycerolmonostearate Beeswax
Ethylene glycoldistearate
12-Hydroxystearicacid
Hydrogenatedcastor oil
Sorbitanmonostearate
Mineral oil L GL L GL GL GL GL
L GL GL GL G GL GLDicaprylyl
carbonateL L L GL GL GL GL
GL GL GL GL G GL GLIsopropyl
myristateGL LS LS GL G GL GLGL GL GL GL G GL GL
Cetylisononanoate
L GL GL GL GL GL GLGL GL GL GL G GL GL
2-Propylheptylcaprylate
L L L GL GL GL GLL GL GL GL G G L
Decyl oleate GL GL GL G GL GL GLL GL GL GL G G GL
Castor oil GL G G G GL GL LG G G GL GL G L
Octyldodecanol GL GL GL G GL GL LSGL GL G GL GL GL LS
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Castor oil gelify without liquid separation with paraffin,hydrogenated castor oil, glycerol monostearate and bees-wax. With paraffin is stable over at least 30 days at room
temperature and at centrifugation and unstable after oneyear at room temperature and three months at 40C. Withglycerol monostearate is unstable after three months at
TABLE 3Stability after one year of storage at room temperature of lipogels that are stable after 30 days of storage at room
temperature: G gel, GL gel and liquid, unstable after 30 days of storage at room temperature; up: slowcooling without stirring; down: quick cooling with stirring
Gelatoroil Paraffin
Glycerolmonostearate Beeswax
Ethylene glycoldistearate
12-Hydroxystearicacid
Hydrogenatedcastor oil
Sorbitanmonostearate
Mineral oil G
Dicaprylylcarbonate
G
Isopropylmyristate
GLG
Cetyl isononanoate G
2-Propylheptylcaprylate
G G
Decyl oleate GL G G
Castor oil GL G GL
GL G G GOctyldodecanol GL
GL
TABLE 4Stability after three months at 40C of lipogels that are stable after 30 days of storage at room temperature: G gel,
GL gel and liquid, unstable after 30 days of storage at room temperature; up: slow cooling without stirring;
down: quick cooling with stirring
Gelatoroil Paraffin
Glycerolmonostearate Beeswax
Ethylene glycoldistearate
12-Hydroxystearicacid
Hydrogenatedcastor oil
Sorbitanmonostearate
Mineral oil G
Dicaprylylcarbonate
G
Isopropylmyristate
GLG
Cetylisononanoate
G
2-Propylheptylcaprylate
G G
Decyl oleate GL G G
Castor oil GL GL GL GL GL G G
Octyldodecanol GLGL
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40C. Lipogels with hydrogenated castor oil and beeswaxare stables in all stability tests.
Octyldodecanol gelifyes without liquid separation withbeeswax. The formed lipogel is unstable after one year atroom temperature and three months at 40C.
Eight formulations are stables in all stability tests: sixwith 12-hydroxystearic acid, one with hydrogenated castoroil and one with beeswax as gelators. The lipogels with12-hydroxystearic acid as gelator dont spread or formclusters that spread after pressing. The two lipogels withcastor oil has a good spreading ability (Table 5).
The ability of 12-hydroxystearic acid to form stable lipo-gels could be able to the hydroxyl group in the atom of car-bon 12. Of accord with Terech[20] the 12-D-hydroxystearicacid gel network consists of long and rigid fibres which areconnected by microcrystalline domains. Rigidity and crys-tallinity of the aggregates are structural features whichaccount for the plastic mechanical behavior of these orga-
nogels. The molecular organization within the gel struc-tures is reminiscent of the monoclinic structure of thesolid state. The 12-D-hydroxystearic acid molecules areconnected by an infinite axial H-bonding sequence withinribbon-like aggregates having polarized interfaces.
The other two good gelators are hydrogenated castor oiland beeswax. Hydrogenated castor oil has also a hydroxylgroup in the atom of carbon 12 of the fatty acid chains but,possibly by steric factors, the gel structure is not rigid as12-hydroxystearic acid gel network. Beeswax also hashydroxy fatty acids.[21,22] The minor capacity to formH-bonds of these gelators is compensate by the presenceof hydroxyl groups in the molecules of castor oil. The good
spread ability of the lipogels of castor oil gellified by hydro-genated castor oil and beeswax could be attributed to theminor rigidity of the gel network.
CONCLUSIONS
12-Hydroxystearic acid forms stable lipogels with oils oflow polarities (solubility parameters between 14.2 to
16.5 MPa0.5), in the meanwhile hydrogenated castor oiland beeswax forms stables lipogels with the more polarcastor oil (solubility parameters 18.2).
The resistance to spread of the lipogels with 12-hydroxystearic acid could be attributed to the rigidity of
the gel network and the good spread ability of the lipogelsof castor oil gellified by hydrogenated castor oil and bees-wax to the minor rigidity of the gel network. Due to itsgood spread ability, the lipogels of castor oil gellified byhydrogenated castor oil and beeswax are the moreadequate for topical application of lipophilic drugs.
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TABLE 5Spreading ability on the skin by pressing with the fingers of lipogels prepared with quick cooling and stirring
that passes all stability tests
Oil Gelator Spreading ability
Mineral oil 12-Hydroxystearic acid Form clusters that spreads after pressingDicaprylyl carbonate 12-Hydroxystearic acid Not spread
Isopropyl myristate 12-Hydroxystearic acid Form clusters that spreads after pressingCetyl isononanoate 12-Hydroxystearic acid Not spread2-Propylheptyl caprylate 12-Hydroxystearic acid Form clusters that spreads after pressingDecyl oleate 12-Hydroxystearic acid Form clusters that spreads after pressingCastor oil Hydrogenated castor oil Good spreadingCastor oil Beeswax Good spreading
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[14] Brosse, N., Barth, D., and Jamart-Gregoire, B. (2004) Tetra-hedron Lett., 45: 95219524.
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