Single- and Two-Step Emulsification To Prepare a Persistent Multiple

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MATERIALS AND INTERFACES Single- and Two-Step Emulsification To Prepare a Persistent Multiple Emulsion with a Surfactant-Polymer Mixture Joachim Allouche,† Eric Tyrode,‡ Ve´ ronique Sadtler,† Lionel Choplin,*,† and Jean-Louis Salager‡ Centre de Ge´ nie chimique des Milieux Rhe´ ologiquement Complexes (GEMICO), Ecole Nationale Supe´ rieure des Industries Chimiques (ENSIC), Nancy, France, and FIRP Laboratory, Universidad de Los Andes, Me´ rida, Venezuela

The regions corresponding to different emulsion morphology occurrences have been clearly identified on a bidimensional formulation-composition map. Multiple emulsions spontaneously form when there is a conflict between the formulation and composition effects. In such systems the most external emulsion is found to be unstable when the formulation effect is produced by a single surfactant. The use of a proper surfactant-polymer mixture allows one to strongly inhibit the mass transfer and to considerably lengthen the equilibration between interfaces. As a consequence, the multiple emulsion can be stable enough to be used in encapsulation and controlled-release applications. The area where multiple emulsions occur and their characteristics (conductivity and amount of encapsulated external phase) are reported for a system containing a sorbitan ester lipophilic surfactant and a diblock poly(ethylene oxide)-poly(propylene oxide) hydrophilic polymer, as a function of the formulation and composition, for a single-step process in which a specific amount of mechanical energy is supplied. An increase in the oil viscosity is found to alter the map and to modify the multiple emulsion characteristics. The application of the results to emulsion-making technology is discussed. Introduction Multiple emulsions of both the water-in-oil-in-water (w/O/W) and the oil-in-water-in-oil (o/W/O) types find many application in cosmetics, pharmaceuticals, agrochemicals, industrial chemicals, etc. In most cases, these systems are prepared according to a two-step process.1-3 For producing a w/O/W emulsion, a primary or inner w/O emulsion is first prepared with a lipophilic surfactant. This emulsion is used as the internal phase to make an O/W so-called outer emulsion by pouring it during stirring in an aqueous phase containing a hydrophilic surfactant. After some time, which can be quite short with low molecular weight amphiphiles, the transfer and partitioning of the two surfactant species reach equilibrium and the formulation becomes the same at all interfaces, whether it is convex or concave toward water. Some authors have shown that multiple emulsions can also be generated during catastrophic or transitional phase inversion4,5 or in the region where there is a conflict between the formulation and composition effects.6 It is known that in this latter case the outer emulsion of the multiple emulsion is generally unstable. This instability is due to the fact that a given surfactant or surfactant mixture is able to stabilize only one type of curvature according to Langmuir’s wedge theory7 or more modern equivalents8 but not both curvatures at * To whom correspondence should be addressed. E-mail: [email protected]. † ENSIC. ‡ Universidad de Los Andes.

the same time. When the emulsion is prepared by a twostep procedure, the equilibration process can be inhibited or slowed, for instance by using high molecular weight polymeric amphiphiles whose transfer rate to the other interface is restricted by kinetic effects. The use of block poly(ethylene oxide) (PEO)-poly(propylene oxide) (PPO) polymers as a kinetic stabilizer of the outer emulsion has been reported,9-11 but very few studies have dealt with the protocol of emulsification for producing a multiple emulsion.12 Because the protocol has to do with the order of introduction of the different substances, it can cause delays and other kinetic effects favorable or not to the end target of stabilizing the multiple emulsion. The aim of the present paper is to report a novel approach for making a multiple w/O/W emulsion using a surfactant-polymer mixture and two different emulsification protocols. The following discussion makes use of the generalized formulation concept and monitors the system evolution on a bidimensional formulation-composition map, whose basics are briefly reviewed next. Generalized Formulation Early formulation concepts such as hydrophiliclipophilic balance (HLB) and phase-inversion temperature (PIT) have been extended into generalized expressions that take into account the effect of all variables.13 Such expressions are the surfactant affinity difference (SAD), i.e., the variation of the chemical potential of a

10.1021/ie0208669 CCC: $25.00 © 2003 American Chemical Society Published on Web 07/22/2003

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Figure 1. Formulation-composition bidimensional map.

surfactant molecule when it passes from the aqueous and oil phases, which can be calculated from the measurement of the partition coefficient of the surfactant between these phases,14 or its adimensional deviation from a reference state, recently defined as the hydrophilic-lipophilic deviation (HLD).15,16 The reference state is taken as the optimum formulation for the attainment of three-phase behavior in the surfactantoil-water system.17 In most instances, the surfactant partitioning coefficient is unity and the SAD is zero in such a reference case, but this is not necessary, as was found for some nonionics.14 For ethoxylated nonionic surfactant-alkane-NaClbrine systems, HLD is written as15,16

HLD ) (SAD - SADref)/RT ) R - EON - kACN + bS + cT(T - 25) (1) where R depends on the hydrophobic part of the surfactant, EON is the number of ethylene oxide groups per surfactant molecule, ACN (alkane carbon number) is a characteristic parameter of the oil, e.g., the number of carbon atoms when it is an alkane, S is the salinity in NaCl (g/100 mL of aqueous phase), and T is the temperature (°C). k, b, and cT are empirical constants that depend on the type of the system. More information may be found elsewhere.13,15 Because HLD contains the same generalized information as Winsor’s R ratio, although this time with a numerical value, it is linked to the phase behavior of the surfactant-oil-water system.17 HLD < 0 (respectively > 0) corresponds to Winsor I or WI (respectively WII) phase behavior. HLD ) 0 corresponds to the socalled optimal formulation (WIII). In the past decades, emulsion properties have been conveniently represented in a bidimensional map as dependent on two variables: the generalized formulation and the water/oil ratio (WOR).18 This map, whose detailed analysis may be found elsewhere,19 has become a handy tool to interpret the evolution of emulsions when submitted to various changes.20,21 These concepts will be used in the following discussion, which can be considered a case of an emerging technological reasoning called formulation engineering (Figure 1).22-24 The central horizontal line corresponds to HLD ) 0, i.e., optimum formulation for three-phase behavior, where the surfactant exhibits an equal affinity for the oil and water phases. Above it (respectively below it), HLD > 0 (respectively HLD < 0) and the affinity of the surfactant for the oil (respectively water) dominates. The bold line is the inversion frontier, that is, the boundary which separates the regions where oil external (W/O) and water external (O/W) emulsions are found

in this map when an equilibrated surfactant-oil-water system, having the corresponding formulation and composition, is stirred. This line is essentially composed of a central horizontal branch and two vertical lateral branches. The central region is labeled A with a + (respectively -) superscript to indicate that the region is located above (respectively below) the optimum or neutral tendency formulation line (HLD ) 0). The lateral branches of the inversion line essentially correspond to a constant WOR, typically located at 30 and 70% water. The left region is labeled B and the right C, both with the same superscript symbol as that in the central region. The B+ region is found to be phenomenologically identical to the A+ region, and there is no real boundary between them but a simple change in WOR. It is the same for the A- and C- regions. All of these A-C- and A+B+ regions are called normal regions because the emulsion type corresponds to the curvature that is favored by the physicochemical formulation effect, a situation which is often referred to as Bancroft’s rule.25,26 On the contrary, the C+ and B- regions are so-called abnormal18 because the external phase is not the one which is expected according to Bancroft’s rule. Instead, it is the external phase favored by Ostwald’s rule; i.e., it is the phase existing in a higher volume in the system.27,28 In these abnormal regions, multiple emulsions are often produced by simple stirring. They are of the o/W/O type in B- and the w/O/W type in C+, where the lower case letter indicates the most internal phase, i.e., the droplets inside the drops. It can be said that the spontaneous occurrence of a multiple emulsion is a way for the system to satisfy conflicting inclinations, as far as interface curvature is concerned. The most interior or “inner” emulsion is of the type imposed by the formulation, e.g., w/O in the C+ region, whereas the external or “outer” one is the type demanded by composition, e.g., O/W in the C+ region. According to the property patterns associated with the location in the map,6,19 the inner emulsion is expected to be stable, while the outer one is likely to coalesce quickly. A w/O/W multiple emulsion prepared in the C+ region is thus inclined to break up first through the coalescence of the outer emulsion to become a two-layer system made of water and oil, with the latter being actually a w/O fine emulsion. This is at least what happens when the system contains a single low molecular weight surfactant. As will be shown in this paper, this general trend can be circumvented using an additional hydrophilic polymer surfactant to stabilize the outer emulsion. Two emulsification protocols for preparing a multiple emulsion with such a surfactant-polymer mixture will be studied. In the first and in the second one respectively, the two surfactants will be associated in the system simultaneously or successively. It will be shown how the final properties of the multiple emulsion, especially the stability and the inner water phase content, depend on the emulsification protocol. Materials and Method The oils are a kerosene cut (EACN ) 9.6) purchased from Fluka Chemika (Germany) and a heavy hydrocarbon oil, “Bright Stock Solvent” (BSS), purchased from Total (France), whose viscosity is 1 Pa‚s at 20 °C and EACN about 16. The lipophilic surfactant is a sorbitan monolaurate (Span 20) purchased from Fluka Chemika (molecular weight ) 346 g/mol and HLB ) 8.6).

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Figure 2. Two-step emulsification procedure to make a multiple emulsion in C+/C-.

The hydrophilic polymeric surfactant is a PEO-PPO block copolymer (Pluronic F68) purchased from Fluka Chemika. It contains 80 wt % of ethylene oxide and has a molecular weight of 8350 g/mol and a HLB of 29. Water is treated by a Milli-Q system (Millipore). The sodium chloride (>99.5%) is of analytical grade from Merck. The emulsification at 25 °C is carried out with an Ultra-Turrax turbine blender model T25 from IKA. The emulsion conductivity is measured with a conductimeter model LF340 and a Tetracon cell 325 manufactured by WTW (Germany). The amount of inner water in a multiple emulsion of the w/O/W type is calculated from the deviation of conductivity from the expected value predicted by Bruggeman’s law given by

κ ) κwfw3/2

(2)

where κ is the emulsion conductivity, κw is the aqueous phase conductivity, and fw is the volume fraction of water in the system. If the experimental value of conductivity is lower than the one expected from Bruggeman’s law, this means that some water is not available to conduct electricity; i.e., it indicates the occurrence of a w/O/W multiple emulsion. Emulsification Protocol Multiple Emulsion Formation in Two Steps (Two-Step Emulsification). The method starts with the emulsification of an equilibrated system in this C+ zone of the bidimensional formulation-composition map (Figure 2). The sample is composed of a small amount of the oil phase containing the Span 20 lipophilic surfactant and of an aqueous phase brine containing 1 wt % NaCl. The concentration of Span 20 is 1 wt % with respect to the total volume of the sample whatever the actual proportion of oil. The initial composition, i.e., the WOR, which is made to vary with the viscosity of the oil phase as discussed later, is selected so that the emulsification always takes place in the C+ zone. This precaution is necessary because the position of the A+/ C+ branch of the inversion line depends on the oil viscosity, among other factors.29,30 The sample is left to equilibrate for 24 h, and the emulsification is carried out with the Ultra-Turrax mixer according to the following standard procedure. The turbine located at the tip of the stirrer stem is positioned at the interface between the oil phase and the aqueous phase, so that the position of the impeller

is expected to have no effect on the emulsion type.10 A first emulsification is carried out at 15 000 rpm for 1 min to form a w/O/W emulsion. From previous research reports, it is known that the inner w/O emulsion is quite stable, whereas the outer O/W emulsion is rather unstable if left at rest. Immediately after the first emulsification is carried out, a certain amount (see below) of hydrophilic polymer is added as an aqueous aliquot, and the stirring is resumed for an additional 1 min at 8500 rpm. The outer O/W emulsion is reformed with an external aqueous phase containing a hydrophilic amphiphile to ensure the proper formulation for its representative point to be located in the C region, where O/W emulsions are known to be stable. At this moment, both the inner and the outer emulsions are stable because the formulation of their interfaces corresponds to the proper HLD. However, the system is out of equilibrium and the two amphiphiles are likely to migrate so that the interfacial composition tends to become the same everywhere in the system, i.e., at both inner and outer emulsion interfaces. Delaying this overall equilibration as long as possible is thus critical to ensure the persistence of the multiple emulsion. The use of a hydrophilic polymer surfactant contributes to this delay because it is a water-soluble substance whose transfer through the oil phase to attain the inner emulsion interface could be very slow. On the other hand, the Span 20 surfactant is a small molecule that is not likely to displace the hydrophilic polymer from the outer emulsion interface once this latter is adsorbed. However, the composition of the outer emulsion interface depends on the adsorption that takes place during the second emulsification process and thus depends on the relative amount of lipophilic and hydrophilic amphiphiles, as well as the water-to-oil ratio. Multiple Emulsion Formation in a Single Step (Single-Step Emulsification). A similar situation can result in a single-step emulsification procedure, thanks to the difference in adsorption and diffusion kinetics of the two amphiphiles. In the following, both the surfactant and polymer are introduced, respectively in oil and water, before a single emulsification procedure is carried out. The formulation/composition location can be anywhere in the map, most particularly in the C+ region where w/O/W emulsions are found to be produced as a consequence of the conflict between formulation and composition effects. The best conditions to attain a persistent multiple emulsion are determined by a bidimensional scanning

Ind. Eng. Chem. Res., Vol. 42, No. 17, 2003 3985 Table 1. Formulation-Composition Scan (One-Step Emulsification) formulation

(vol % of inner aqueous phase) morphology

wt %

mol %

WOR (water/kerosene)

Span 20

Pluronic F68

Span 20

Pluronic F68

25/75 ) 0.3

50/50 ) 1

75/25 ) 3

100 80 60 40 20 0

0 20 40 60 80 100

100 99 97 86 86 0

0 1 3 14 14 100

W/O W/O W/O W/O (1.5) w/O/W O/W

W/O (25.4) w/O/W (12.6) w/O/W (4.9) w/O/W (7.1) w/O/W O/W

W/O (10.6) w/O/W (5.9) w/O/W (5.3) w/O/W (5.7) w/O/W O/W

of the surfactant/polymer ratio, i.e., formulation, and of the WOR, i.e., composition. Three values are taken for the WOR, e.g., 75/25, 50/ 50, and 25/75. The proportion of lipophilic surfactant (Span 20) and hydrophilic polymer (Pluronic F68) is varied from 0 to 100 wt % with respect to the total concentration of the surfactant-polymer mixture, which is selected as 2 wt % with respect to the total volume of the sample. The samples are equilibrated for 24 h. The two amphiphiles are quite different in hydrophilicity, and as usual in these cases there is a strong partitioning31 and no three-phase behavior is exhibited at optimum formulation, which is located by the interfacial tension minimum and the overall surfactant partitioning detected by light scattering and from the emulsified system by the stability minimum and by the middle of the conductivity variation when the range is not too large.32 For the WOR ) 50/50 case, optimum formulation, i.e., HLD ) 0, is at about 30-35 wt % polymer, a value which is consistent with the fact that polymer is very hydrophilic, whereas the surfactant is only slightly hydrophobic. In any case, the exact position of HLD ) 0 at low and high WOR is not critical because the inversion line is known to cross the optimum phase behavior close to WOR ) 1,6,18 and the interpretations are based on the results after emulsification of the samples carried out with the Ultra-turrax blender at 5000 rpm for 1 min. The emulsion morphology is determined by measuring the conductivity under magnetic mixing. The stability of each sample is evaluated after 24 h of rest by measuring the separated volume (Vsep) of the oil phase, which corresponds to the volume of the completely broken oil droplets. The total volume of the samples is 50 mL; this means that, for WOR ) 50/50, the maximal value of the separated oil is 25 mL. Results Formulation-Composition Scanning and SingleStep Procedure. Table 1 data indicate that in the two extreme cases, i.e., 100 wt % lipophilic surfactant or 100 wt % hydrophilic polymer, the formulation effect commands the emulsion morphology, which is respectively w/O and O/W. This means that the A+ and A- central zones extend at least over the 25-75% range of water at the HLD values corresponding to each of the two substances. When both surfactant and polymer are present, w/O/W multiple emulsions are generated at intermediate and high water content, as well as for 25% water for the 20 wt % lipophilic surfactant case. This means that the lipophilic surfactant is always able to produce a w/O emulsion somewhere in the system. This result is attributed to the surfactant low molecular weight (345 g/mol) compared to the polymer one (8350 g/mol), which ensures a rapid diffusion and adsorption

Figure 3. Emulsion stability for WOR ) 50/50.

of the surfactant at the interface to favor the corresponding interfacial curvature. Besides, the corresponding relative amount of surfactant in mole percent reveals with evidence that the molecular content of the lipophilic surfactant in the system is much higher compared to that of the polymer. This is especially very significant at low Span 20 concentration such as 20 wt %, which corresponds to 86 mol %. This W/O morphology corresponds to the overall emulsion if there is enough oil and enough surfactant, or it becomes the inner w/O emulsion when the conditions (high water content or high hydrophilic polymer content) command the formation of an O/W outer emulsion. An accurate conductivity measurement allows one to determine the inner water content by comparing it to the conductivity expected from Bruggeman’s law for a simple O/W emulsion. Numbers in parentheses in Table 1 indicate the volume percentage of the inner phase, i.e., corresponding to the water (w) droplets inside the oil (O) drops. For intermediate and high water content systems, the w inner phase volume rises as the lipophilic surfactant percentage increases. Just before the emulsion turns into a simple W/O type, the amount of inner water is maximum (25.4 vol %) for a 80 wt % lipophilic surfactant at unit WOR. This means that in this case the water splits into essentially equal volumes of inner w and outer W phases. Figure 3 illustrates the settling of the oil phase from the emulsion with unit WOR at different surfactant/ polymer proportions. The separated volume (measured with graduated vials) corresponds to the coalescence of the oil drops in the outer O/W emulsion. As expected, it is larger when there is less, e.g., 20 wt %, of the hydrophilic polymer. Stability increases further when more and more polymer is introduced but at the expense of the production of a lesser amount of inner w phase. It is thus clear that the role of the two amphiphiles is segregated, with the lipophilic surfactant favoring the inner emulsion persistence and the hydrophilic polymer the outer one. At 40 wt % polymer for unit WOR, a good

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Figure 4. Shifting of the inversion line by oil viscosity variation.

Figure 5. Conductivity measurements for different oil viscosities. Table 2. Determination of the Best Surfactant/Polymer Ratio WOR (water/kerosene) 50/50 wt % Span 20

wt % polymer

% of inner phase

80 60 40

20 40 60

25.4 12.6 4.9

75/25 % of inner phase

3.92 1.96 0.98 Vsep (mL) stability

10.6 5.9 5.3

stabilization is attained for a multiple emulsion containing about 10% of the inner w phase. If the WOR is increased to 75/25, the stability is even increased, at the expense of a reduced (about 6%) amount of the inner w phase, at least in the conditions of emulsification. These results allow one to find the best surfactant/ polymer ratio which corresponds to some kind of compromise between the inner w phase content and the persistence of the multiple emulsion. If a reasonable stability is required, the 75% water content is warranted, provided that it locates the system in the C region of the formulation-composition map, probably with the inner emulsion in C+ and the outer one in C-. In such a case, Table 2 indicates that the best compro-

0.98 0.49 0 Vsep (mL) stability

too low stability optimal surfactant/polymer ratio too low inner phase content

mise between a not-too-low stability and not-too-low inner phase content could be 40 wt % of polymer, or may be 60%. Effect of the Viscosity of the Oil Phase. According to the previously mentioned one-step method, multiple morphology spontaneously takes place when the emulsification is carried out in the C+ region, i.e., on the right side of the A+/C+ branch of the inversion line. On the other hand, it has been known for some time that the A+/C+ branch can be shifted toward the left, i.e., to a lower volumic fraction of water (fw) by increasing the oil viscosity (ηo).18,30 Figure 4 shows that such a trend is corroborated in the present system, at least in the shown range. In these

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experiments, the oil viscosity is changed by mixing a viscous hydrocarbon oil (BSS) with kerosene. Composition scans are carried out in the HLD > 0 region (1 wt % lipophilic surfactant) to determine the boundary between the A+ and C+ regions. When the oil viscosity increases from 1 to 5 cP, the A+/C+ branch of the inversion line is shifted from fw ) 0.8 to 0.4. This means that increasing the viscosity of the oil phase extends the C+ zone, which is favorable to attain the w/O/W multiple morphology. However, too large an increase in the oil viscosity, i.e., beyond 5 cP, could be detrimental because the inner emulsion becomes more difficult to produce. A change in the oil nature also can change the formulation through the HLD expression, and for the sake of simplicity, it is better not to extrapolate to far. Indeed, for ηo ) 20 cP, some amount of water appears to be dispersed in the oil phase and a simple W/O emulsion as well as the multiple emulsion is generated, at least in the conditions of emulsification. The following discussion will thus be carried for an oil viscosity ranging from 1 to 5 cP. It is worth noting that the mixing of the two oils changes not only the viscosity but the EACN too. However, the EACN variation is small in the studied range and the formulation is maintained at HLD > 0, far away from HLD ) 0 in all cases. Two-Step Emulsification Procedure. According to the Figure 4 results, it is possible to form a multiple w/O/W emulsion with different values of the oil viscosity by adjusting the WOR of the sample. For the three different oil viscosity values 1, 1.7, and 5 cP, samples are prepared respectively at fw ) 0.85, 0.6, and 0.5 and the two-step emulsification procedure is carried out. According to the optimal surfactant/polymer ratio determined before, stabilization of the w/O/W emulsion during the second emulsification is performed by the addition of 40 wt % of the hydrophilic polymer with respect to the total surfactant-polymer concentration. Conductivity measurements exhibited in Figure 5 show that the deviation from the O/W morphology expected value (dashed line) decreases when the oil viscosity increases. This indicates that the percentage of inner water decreases as the oil viscosity increases. It is 28% vol % for ηo ) 1 cP and plummets at 15.8 vol % for ηo ) 5 cP. The data also corroborate that the normal A+ region shrinks considerably as the oil viscosity is increased. This is consistent with the well-known trend that it is always easier to disperse a viscous phase in a nonviscous one than the opposite. Accordingly, the O/W morphology would be more and more favored as the oil viscosity increases, despite being the abnormal one. This effect can be used to reduce the amount of inner phase, or in contrary it would have to be offset somehow, for instance, by changing the stirring conditions, if it is detrimental. Conclusion The use of an amphiphile mixture composed of a lipophilic surfactant and a hydrophilic polymer allows one to make a persistent w/O/W multiple emulsion in a one- or two-step emulsification process. It was shown how the preparation protocol, monitored in a formulation-composition map, can affect the emulsion properties. Specifically, it is shown how the inner water phase content and the outer emulsion stability change with formulation, composition, and oil viscosity in a way

which is consistent with the general phenomenology on emulsion properties. Acknowledgment CONICIT/FONACIT (Venezuela) and MAE (France) are thanked for sponsoring the exchanges of the junior researchers (J.A. and E.T.) through the Postgraduate Cooperation Program PCP. Financial support was provided by FONACIT Grants AP-97-3719 and S1-01-0156 and Universidad de Los Andes Grant CDCHT-I-635-99. Literature Cited (1) Florence, A. T.; Whitehill, D. The Formulation and Stability of Multiple Emulsions. Int. J. Pharm. 1982, 11, 277. (2) Prybilski, C.; Luca, M. d.; Grossiord, J. L.; Vaution, C.; Seiller, M. W/O/W Multiple Emulsions: Manufacturing and Formulation Considerations. Cosmet. Toiletries 1991, 106, 97. (3) Okochi, H.; Nakano, M. Basic Studies on Formulation, Method of Preparation and Characterization of Water-in-Oil-inWater Type Multiple Emulsions Containing Vancomycin. Chem. Pharm. Bull. 1996, 44, 180. (4) Matsumoto, S. Development of W/O/W-Type Dispersion during Phase Inversion of Concentrated W/O Emulsions. J. Colloid Interface Sci. 1982, 94, 362. (5) Matsumoto, S.; Koh, Y.; Michiura, A. Preparation of W/O/W Emulsions in an Edible Form on the Basis of Phase Inversion Technique. J. Dispers. Sci. Technol. 1985, 6, 507. (6) Minãna-Perez, M.; Jarry, P.; Perez-Sanchez, M.; RamirezGouveia, M.; Salager, J. L. Surfactant-Oil-Water Systems near the Affinity InversionsPart V: Properties of Emulsions. J. Dispers. Sci. Technol. 1986, 7, 331. (7) Langmuir, I. The Constitution and Fundamental Properties of Solids and Liquids. II. Liquids. J. Am. Chem. Soc. 1917, 39, 1848. (8) Kalbanov, A.; Wennerstro¨m, H. Macroemulsion: The Oriented Wedge Theory Revisited. Langmuir 1996, 12, 276. (9) Py, C.; Rouvie`re, J.; Loll, P.; Taelman, M. C.; Tadros, T. F. Investigation of Multiple Emulsion Stability using Rheological Measurements. Colloids Surf. A 1994, 91, 215. (10) Doucet, O.; Ferrero, L.; Garcia, N.; Zastrow, L. O/W Emulsion and W/O/W Multiple Emulsion: Physical Characterization and Skin Pharmacokinetic Comparison in the Delivery Process of Caffeine. Int. J. Cosmet. Sci. 1998, 20, 283. (11) Denine, R.; Jager-Lezer, N.; Grossiord, J. L.; Puiseux, F.; Seiller, M. Influence de la Formulation d’une Emulsion Multiple Cosme´tique sur la Libe´ration des Actifs Encapsule´s. Int. J. Cosmet. Sci. 1996, 18, 103. (12) Salager, S. E.; Tyrode, E.; Celis, M. T.; Salager, J. L. Influence of the Stirrer Initial Position on Emulsion Morphology. Making use of the Local Water-to-Oil Ratio Concept for Formulation Engineering Purpose. Ind. Eng. Chem. Res. 2001, 40, 4808. (13) Salager, J. L. Microemulsions. In Handbook of Detergentss Part A: Properties; Broze, G., Ed.; Marcel Dekker: New York, 1999; Chapter 8. (14) Ma´rquez, N.; Antoń, R. E.; Graciaa, A.; Lachaise, J.; Salager, J. L. Partitioning of ethoxylated alkylphenol surfactants in microemulsions-oil-water systems. Colloids Surf. A 1995, 100, 225-231. (15) Salager, J. L.; Antoń, R. A.; Ande´rez, J. M.; Aubry, J. M. Formulation des Micro-e´mulsions par la Me´thode HLD. Technique de l’Inge´ nieur; vol. Geńie des proce´de´s; Paris, 2001; Chapters J2157. (16) Salager, J. L.; Ma´rquez, N.; Graciaa, A.; Lachaise, J. Partitionnig of Ethoxylated Octylphenol Surfactants in Microemulsion-oil-water Systems. Influence of Temperature and Relation between Partitioning Coefficient and Physicochemical Formulation. Langmuir 2000, 16, 5534. (17) Bourrel, M.; Schechter, R. S. Microemulsion and Related Systems; Marcel Dekker: New York, 1988. (18) Salager, J. L.; Minãna-Pe´rez, M.; Pe´rez-Sanchez, M.; Ramirez-Gouveia, M.; Rojas, C. Surfactant-Oil-Water Systems near the Affinity InversionsPart III: The Two Kinds of Emulsion Inversion. J. Dispers. Sci. Technol. 1983, 4, 313. (19) Salager, J. L. Emulsion Properties and Related Know-how to Attain them. In Pharmaceutical Emulsions and Suspensions;

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Received for review October 31, 2002 Revised manuscript received May 7, 2003 Accepted May 8, 2003 IE0208669

Single- and Two-Step Emulsification To Prepare a Persistent Multiple

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