Diffusion from Hydrogenated and Fluorinated Gel−Emulsion Mixtures

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Diffusion from Hydrogenated and Fluorinated Gel-Emulsion Mixtures G. Caldero´,*,† M. J. Garcı´a-Celma,† C. Solans,† M. J. Ste´be´,‡ J. C. Ravey,‡ S. Rocca,‡ and R. Pons† Departament de Tecnologia de Tensioactius, CID/CSIC, Jordi Girona 18-26, 08034 Barcelona, Spain, and Groupe Physico-Chimie des Colloı¨des, LESOC, CNRS, URA 406, Universite´ de Nancy I, Henri Poincare´ B.P. 239, 540506 Vandoeuvre les Nancy Cedex, France Received June 20, 1997. In Final Form: December 19, 1997 Highly concentrated water-in-oil gel-emulsions consisting of mixtures of hydrogenated and fluorinated gel-emulsions were prepared by two different procedures. Diffusion of a model molecule from the gelemulsion mixtures was studied and compared with those of hydrogenated and fluorinated systems. The stability of the mixed gel-emulsions was assessed and related to the diffusion coefficients. Diffusion experiments were carried out by two different methods, and diffusion coefficients were determined by numerical solution. In one experimental method the diffusion to a receptor solution was measured while in the other method the diffusion of the model molecule within the emulsion was determined. The results show that it is possible to control the stability and to obtain intermediate diffusion rates using appropriate gel-emulsion mixtures.

Introduction Gel-emulsions are highly concentrated water-in-oil emulsions which can be formed in ternary water-nonionic surfactant-oil systems. They can be formulated with an extraordinarily large water content (i.e. 99%) and a very low surfactant concentration (i.e. below 0.5% w/w). Water can be dispersed both in hydrocarbon-hydrogenated surfactant1-5 and in fluorocarbon-fluorinated surfactant mixtures.6-8 These emulsions form above the hydrophilic-lipophilic balance (HLB) temperature of the corresponding system, and their stability is maximum at about 25 °C above this temperature. Gel-emulsions consist of two isotropic liquid phases: one is a submicellar surfactant solution in water, and the other is a swollen reversed micellar solution or water-in-oil (w/o) microemulsion.6,7,9,10 Structurally, gel-emulsions contain two kinds of water droplets:9,11 a small droplet size population (R ∼ 0.01 µm) corresponding to the w/o swollen reversed micellar solution and a more polydisperse population of polyhedral droplets with mean sizes ranging from 0.5 to 5 µm. These systems can be considered as a water in a w/o microemulsion emulsion. The aspect of the gelemulsions viewed under the microscope is foamlike. The * To whom correspondence should be addressed. Telephone: 343-4006100. Fax: 34-4-2045904. E-mail: [email protected]. † CID/CSIC. ‡ Universite ´ de Nancy I. (1) Kunieda, H.; Solans, C.; Shida, N.; Parra, J. L. Colloids Surf. 1987, 24, 225. (2) Solans, C, Garcı´a-Domı´nguez, J. J.; Parra, J. L., Heuser, J., Friberg, S. E. Colloid Polym. Sci. 1988, 266, 570. (3) Kunieda, H.; Yano, N.; Solans, C. Colloids Surf. 1989, 36, 313. (4) Kunieda, H.; Evans, D. F.; Solans, C.; Yoshida, M. Colloids Surf. 1990, 47, 35. (5) Solans, C.; Comelles, F.; Azemar, N.; Sa´nchez-Leal, J.; Parra, J. L. Jorn. Com. Esp. Deterg. 1986, 17, 109. (6) Ravey, J. C.; Ste´be´, M. J.; Sauvage, S. Colloids Surf. 1994, 91, 237. (7) Ravey, J. C.; Ste´be´, M. J. Prog. Colloid Polym. Sci. 1990, 82, 218. (8) Ravey, J. C.; Ste´be´, M. J.; Sauvage, S. J. Chim. Phys. 1994, 91, 259. (9) Pons, R.; Ravey, J. C.; Sauvage, S.; Ste´be´, M. J.; Erra, P.; Solans, C. Colloids Surf. 1993, 76, 171. (10) Pons, R.; Ravey; J. C.; Ste´be´, M. J.; Erra, P.; Solans, C. J. Phys. Chem. 1993, 97, 2320. (11) Plucinski, P.; Nitsch, W. J. Colloid Interface Sci. 1992, 154, 104.

crowding of the droplets gives rise to an elastic behavior that makes the emulsions look gel-like with viscoelastic properties.1-4,9,10,12 The formation of highly concentrated water-in-oil emulsions (gel-emulsions) is a subject which has attracted increasing attention in the past few years both for fundamental and applied interest.1-4,6,9,10,12,13-17 It is possible to prepare very stable emulsions which can be stored for several months or years. These viscoelastic emulsions could be considered appropriate as pharmaceutical or cosmetic delivery systems for the controlled release of hydrophilic or lipophilic compounds. Waterin-oil emulsions constitute a barrier for the release of water-soluble drugs because they have to go through the oily phase. Hydrogenated gel-emulsions can be prepared with a wide variety of compounds, some of them suitable for pharmaceutical and cosmetic purposes.18 Some fluorinated compounds have also been proved to be biocompatible and have already found application as biomedical materials due to their ability to dissolve great amounts of oxygen.19 In this paper we present for the first time results on the formation, preparation, and transport properties of mixtures of hydrogenated and fluorinated, highly concentrated emulsions. It should be emphasized that hydrocarbon and fluorocarbon oils are mutually insoluble at room temperature.20 The data available do not allow us to characterize the structure of such mixed gel-emulsions. (12) Solans, C.; Pons, R.; Zhu, S.; et al. Langmuir 1993, 9, 1479. (13) Bampfield, A.; Cooper, J. In Encyclopedia of Emulsion Technology; Becher, Ed.; Marcel Dekker Inc.: New York, 1988; Vol. 3, pp 281306. (14) Kizling, J.; Kronberg, B. Colloids Surf. 1990, 50, 131. (15) Ruckenstein, E.; Ebert, G.; Platz, G. J. Colloid Interface Sci. 1989, 133, 432. (16) Nixon, J.; Beerbower, A.; Wallace, T. J. Emulsified Fuel for Military Aircraft; ASME Transactions 1968; ASME Preprint No. 68GT-24. (17) Beerbower, A.; Nixon, J.; Wallace, T. J. J. Aircraft 1968, 5, 367. (18) Solans, C.; Carrera, I.; Pons, R.; Erra, P.; Azemar, N.; Kunieda, H. Cosmet. Toiletries 1993, 108, 61. (19) Hamza, M. A.; Serratrice, G.; Ste´be´, M. J.; Delpuech, J. J. J. Am. Chem. Soc. 1981, 103, 3733. (20) Murkerjee, P. J. Am. Oil Chem. Soc. 1982, 59 (12), 573.

S0743-7463(97)00659-8 CCC: $15.00 © 1998 American Chemical Society Published on Web 02/27/1998

Hydrogenated and Fluorinated Gel-Emulsion Mixtures

Nevertheless, there may be two possible structures. One assumes the formation of a new mixed interfacial film containing hydrogenated surfactant molecules and fluorinated surfactant molecules. The other possibility considers the formation of separated hydrogenated and fluorinated domains, which can, in turn, adopt different structures: hydrogenated gel-emulsion domains incorporated in the fluorinated gel-emulsion, fluorinated gelemulsion domains incorporated in the hydrogenated gelemulsion, and a bicontinuous mixture of hydrogenated and fluorinated domains. In the past few years, some studies have been performed that give some information about the interfacial films formed by hydrogenated and fluorinated components in emulsions, surfactant bilayers, and vesicles. These studies show, by several techniques (cmc data, conductivity, DSC, freeze-fracture electron microscopy), that when hydrogenated and fluorinated surfactants with the same charged head-groups (anionicanionic, cationic-cationic, nonionic-nonionic) are mixed, they tend to form separated domains.21-23 Nevertheless, it has been proposed that the mixing of nonionic fluorinated and hydrogenated surfactants in aqueous media remains almost ideal in concentrated systems, although in the absence of oil.24 To our knowledge, there are no other systems in which these two compounds have been mixed in an oil-continuous material. To do so, we have used mixtures of hydrocarbonated and fluorocarbonated surfactants with compatible polar head-groups of the ethylene oxide type. Our earlier studies on hydrogenated gel-emulsions showed that properties such as stability and appearance were highly dependent on composition variables, the chemical structure of the constituents, temperature, additives, and so forth.3,4,7 In this case, diffusion of some water-soluble molecules through their interfaces is rather fast.25,26 In contrast, fluorinated gelemulsions show higher stability10 while diffusion processes have been seen to be considerably slower. Therefore it could be anticipated that it would be possible to modulate the properties of these systems with formulations consisting of a mixture of both types of emulsions. To study diffusion from gel-emulsions, mandelic acid (R-hydroxyphenylacetic acid, referred to in the following as MA) was chosen as a model molecule for the release studies from gel-emulsions. This compound is watersoluble and has very low solubility in aliphatic hydrocarbons. However, due to the presence of an aromatic ring, MA has some affinity for the ethylene oxide groups of the surfactant.27,28 MA has the advantage of being suitable for UV detection. Our first release studies on mixtures of hydrogenated and fluorinated highly concentrated water-in-oil emulsions are reported. Release studies have been performed by means of two different methods designed especially for our purposes. (21) Kunitake, T. Angew. Chem., Int. Ed. Engl. 1992, 31, 709. (22) Ebert, R.; Folda, T.; Ringsdorf, H. J. Am. Chem. Soc. 1984, 106, 7687. (23) Mukerjee, P.; Yang, A. J. Phys. Chem. 1976, 80, 1388. (24) Ravey, J. C.; Gherbi, A.; Ste´be´, M. J. Prog. Colloid Polym. Sci. 1991, 84, 95. (25) Pons, R.; Caldero´, G.; Garcı´a-Celma, M. J.; Azemar, N.; Carrera, I.; Solans, C. Prog. Colloid Polym. Sci. 1996, 100, 132. (26) Caldero´, G.; Garcı´a-Celma, M. J.; Solans, C.; Plaza, M.; Pons, R. Langmuir 1997, 13, 385. (27) Podzimek, M.; Friberg, S. E. J. Dispersion Sci. Technol. 1980, 1, 341. (28) Ravey, J. C. In Nonionics in microemulsions: Structures and Dynamics; Friberg, S. E., Bothorel, P., Eds.; CRC Press: Boca Raton, FL, 1987; pp 93-117.

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Figure 1. Experimental setup described as “method I”. See text for details.

Experimental Section Materials. Mandelic acid (puriss. p.a. >99%; MA) and decane (purum >99%) were purchased from Fluka, and perfluorodecalin was from Ventron Alfa Produkte (Germany). They were used as received. The fluorinated surfactant RfE2 has a polydisperse chain (CmF2m+1C2H4SC2H4(OC2H4)2OH, where m ) 8, 10, 12). It has been synthesized by IRCHA (France) according to a method developed by Cambon et al.29 The hydrogenated surfactant, tetraethylene glycol mono-n-hexadecyl ether (C16E4) was from Nikko Chemicals Co. Ltd. (Japan). Water was MilliQ filtered. Methods. Diffusion Experiments. (i) Method I: Diffusion to a Receptor Solution (Diffusion Cell). This method provides information about the release of MA from a gel-emulsion to an aqueous receptor solution. Our experimental setup is shown in Figure 1. Gel-emulsions are in direct contact with the receptor phase (no separating membranes are present). The setup consists of a three-diffusion-cell assembly. Shallow Teflon cups provided with a glass shaft are filled with 1.5 g of gel-emulsion. The cups are immersed in 35 cm3 of water, which is the receptor solution. The diffusion cells consist of a cylindrical glass vessel thermostated at 25 °C. The receptor solution is gently stirred by means of a paddle stirring element rotated by a motor connected with a speed-regulating device; samples are withdrawn for determination of MA concentrations by UV-spectrophotometry and HPLC. The spectrophotometric analysis is performed immediately. An aliquot is kept for a second analysis by HPLC, and the remaining volume is returned into the diffusion cell together with the same volume of pure water in order to maintain the volume of receptor solution constant. At the beginning, samples are taken every few minutes to establish accurately the MA release in the early stage. In the late stage, when the kinetic profile slows down, the sampling is spaced. (ii) Method II: Diffusion within the Gel-Emulsion (Diffusion Box).25 This method provides information about the diffusion of MA in the gel-emulsion itself. For this purpose, a gel-emulsion composition (mixed or not) containing MA is put in contact with the same gel-emulsion without MA. The setup consists of a small propylene box (4 cm × 2 cm × 2 cm) with nine equidistant grooves in which disposable glass slides can be fitted, giving rise to 10 identical compartments. At the beginning of the experiment only the central glass slide is placed, dividing the box into two compartments. About 8 g of each gel-emulsion is weighed respectively into each compartment, and at time zero the glass slide separating both compartments is removed, allowing for the diffusion of the MA. The experiment is run for at least 15 h, and diffusion is stopped by introducing glass slides into the grooves. A sample is withdrawn from each compartment and analyzed for MA content by UV-spectrophotometry. Analysis. (i) UV-Spectrophotometry. (i) Spectrophotometric analysis was performed using a Shimadzu UV-265FW spectrophotometer. MA in water displays a principal absorption peak at a wavelength of 257 nm. (ii) High-Performance Liquid Chromatography (HPLC). The chromatographic system consisted of an autoinjector (Promis Spark Holland B. V.), a 5 µm × 15 cm × 0.46 cm Spherisorb ODS 2 column, a LC pump (Kontron Instruments, Model T-414), a UV detector set at 257 nm (Kontron Instruments, Model 432), and (29) Cambon, A.; Delpuech, J. J.; Matos, L.; Serratrice, G.; Szonyi, F. Bull. Soc. Chim. 1986, 6, 965-970.

1582 Langmuir, Vol. 14, No. 7, 1998 an integrator (Merck Hitachi, Model D-2500). Separation was carried out at room temperature using methanol-phosphoric acid-water (200:1:799 v/v/v) as mobile phase. The flux rate was set at 0.6 mL/min. The injection volume was 25 µL. The MA retention time was 4 min. Deternination of Diffusion Coefficients. The experimental results of MA release as a function of time were compared to the numerical solution.25 Diffusion coefficients were determined from the experimental results according to two different procedures specific to each experimental method. The concentration-time curves obtained from method I (diffusion cell setup) were fitted to curves calculated by the numerical solution of Fick’s first law with the appropriate boundary conditions for the problem. That is, the initial concentration in the gel-emulsion is constant and equal to C0, and the initial concentration in the solution is zero. The evolution as a function of time is calculated with the additional condition of homogeneity of the receptor solution, that is, dC/dx ) 0, where x is the distance from the surface of the gel-emulsion. As observed in other studies,25 the theoretical curves adequately fit the experimental curves for the hydrogenated gel-emulsions. The initial rate of release is fast, and after some time a plateau is attained; at this time the equilibrium concentration is reached. The diffusion coefficients are obtained by scaling the dimensions of the experimental setup (depth of the cell and volume of the receptor solution) and the time scale to the dimensions used in the calculations. The procedure in treating the data obtained from method II (diffusion-box setup) is different. This diffusion problem has an analytical solution for the boundary conditions (dC/dt)x)(∞ ) 0, where t is time. Under these conditions C ) C0 [1 - erf(x/(4Dt)1/2)]/ 2, where D is the diffusion coefficient.30 In our experimental setup these conditions are approximately met at short times, provided that the variation in concentration at the extreme points of the box has not appreciably changed in the experimental time. If the boundary conditions for the analytical solution are not met, a numerical solution has to be used with the following boundary conditions: initial concentrations for x < 0, C ) C0 and x > 0, C ) 0 and the flux conditions dC/dx ) 0 at the two limits of the diffusion box. The numerical and analytical solutions are coincidental within 1% if the concentrations at the extremes of the box have varied less than a 2%. Stability Assessment. Stability was quantified by means of conductivity measurements as a function of time. Gel-emulsions containing MA were prepared and put in a thermostated water bath at 25 °C. The conductivity of the w/o gel-emulsions is initially low and increases as a function of time when water droplets of the dispersed phase break. Conductivity was measured with a Crison 525 conductimeter and a CDC241U conductivity cell (Radiometer Analytical). The data were transferred to a computer allowing for continuous recording.

Results Hydrogenated and fluorinated gel-emulsion mixtures could be prepared by two different procedures. One procedure consisted of preparing binary oil-surfactant mixtures of the hydrogenated and fluorinated components, followed by addition of the hydrogenated binary mixture over the fluorinated one under continuous stirring and finally addition of the aquous phase (a 1.5% MA aqueous solution). The other procedure, which was the one used for the release studies, consisted of adding appropriate amounts of a fluorinated gel-emulsion slowly under stirring to a hydrogenated gel-emulsion. The aqueous component in both procedures as well as both types of gel-emulsions was 95 wt % of a 1.5 wt % MA solution. The surfactant-to-oil weight ratio was 40:60 for the hydrogenated gel-emulsion and 30:70 for the fluorinated gel-emulsion. The visual aspects of the gel-emulsions were very different from one another. The hydrogenated emulsion was white while the fluorinated emulsion was transparent. Their consistencies were also different; that (30) Cussler, E. L. In Diffusion, Mass transfer in fluid systems; Cambridge University Press: Cambridge, U.K., 1984; Chapter 3.

Caldero´ et al.

Figure 2. Comparison of the conductivity of the tested gelemulsions (in microsiemens per centimeter) as a function of time (in seconds).

of the fluorinated gel-emulsion was higher. The visual aspect and the consistency of the mixed gel-emulsions were intermediate to those of both types of emulsions. Concerning stability, no significant macroscopic changes were observed over 1 month in the fluorinated emulsion, while the hydrogenated emulsion showed phase separation after 1 week. Information about the stability was obtained from conductivity measurements as a function of time. This is shown in Figure 2 for the hydrogenated and fluorinated systems and for their mixtures. As expected for w/o emulsions, all systems have low conductivity at the start point of the experiment. However the evolution of the conductivity with time shows differences. After 34 h the conductivity of the hydrogenated and fluorinated systems is below 0.5 µS/cm while that of the mixture H/F ) 25/75 is about 2.5 µS/cm. These differences are probably related to the coalescence of water droplets and possibly to the formation of water channels. The diffusion of MA from hydrogenated, fluorinated, and mixed gel-emulsions was studied as a function of time. As described in the Experimental Section, two types of diffusion experiments were performed. In method I the emulsions were in contact with a receptor solution without any membrane between them. In method II a gel-emulsion containing MA was brought into contact with a gel-emulsion with the same composition except for the additive. In Figure 3 MA concentration in the receptor solution as a function of time is shown for hydrogenated and fluorinated systems and their mixtures. These results were obtained using diffusion method I. The initial release is fast and slows down progressively. A plateau is reached when the equilibrium concentration is attained. It can be noticed that under these experimental conditions the plateau is not fully reached after 8 days of release in the fluorinated gel-emulsion, in contrast to the approximately 24 h needed by the hydrogenated emulsion. For hydrogenated and fluorinated gel-emulsion mixtures, the drug release rate is strongly dependent on the mixture composition. The more fluorinated the mixture, the slower the diffusion. In any case, considering the three replicates, there is a good reproducibility of the results, especially at the initial stage. When the experimental results were compared with theoretical curves obtained for a simulated release, based on Fick’s law, as described in the Experimental Section,

Hydrogenated and Fluorinated Gel-Emulsion Mixtures

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Figure 3. Experimental data of MA release as a function of time and best mean fitting curves of the three replicates of the following gel-emulsions: (a) H/F ) 100/0; (b) H/F ) 75/25; (c) H/F ) 50/50; (d) H/F ) 25/75; (e) H/F ) 0/100.

a good agreement was obtained for the hydrogenated (Figure 3a) and fluorinated (Figure 3e) systems as well as for the H/F ) 75/25 mixture (Figure 3b). However the experimental results obtained with the other mixed emulsions did not follow the theoretical behavior. This is clearly seen in Figure 3c, which shows the experimental results for the mixture H/F ) 50/50 and in Figure 3d for the mixture H/F ) 25/75. Considering separately the results at short times (up to about 5 × 104 s) and those at longer times (from about 8 × 104 s), two different curves could be fitted (Figure 4) with calculated values of the diffusion coefficient of D ) 0.77 × 10-10 m2/s and D ) 1.11 × 10-10 m2/s, respectively, for a mixed H/F ) 50/50 gelemulsion. Figure 5 shows a typical concentration profile obtained by method II. The diffusion time was adjusted for each composition in order to make possible an analytical solution of Fick’s second law according to the established boundary conditions, as explained earlier25 and in the Experimental Section. As can be seen, the concentrations at the extreme points of the box (x ) -0.018 m and x )

Figure 4. Same data as in Figure 3c (mixed gel-emulsion H/F ) 50/50) showing the best fitting curve at short and long times.

0.018 m) have not appreciably changed. The diffusion coefficients of MA in the gel-emulsion itself obtained by

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Caldero´ et al.

Figure 5. Concentration profile corresponding to the diffusion of MA in a H/F ) 50/50 gel-emulsion mixture (diffusion time ) 15 h). The points are the experimental data, and the line correponds to the best fitting curve. Table 1. Mean Diffusion Coefficients in Square Meter per Second of the Gel-Emulsions Studieda H/F

Db (×10-10 m2/s)

De (×10-10 m2/s)

Dbox (×10-10 m2/s)

100/0 75/25 60/40 50/50 35/65 25/75 10/90 0/100

1.9 ( 0.9 1.9 ( 0.9

1.6 ( 0.8 1.9 ( 1.9

0.7 ( 0.3

1.1 ( 0.2

0.5 ( 0.7

1.1 ( 0.7

0.2 ( 0.4

0.1 ( 0.06

3.05 3.44 4.68 4.3 6.04 9.18 34.8b 0.24

a

Db are the diffusion coefficients obtained from method I fitting the beginning of the curve. De are the diffusion coefficients obtained from method I fitting the end of the curve. Dbox are the diffusion coefficients obtained from method II. Standard deviations of the triplicate data obtained in method I were calculated by means of the Student’s t method. b Value higher than the MA diffusion coefficient in water attributed to convection.

this method (see Table 1) seem not to be much influenced by the amount of fluorinated gel-emulsion in the mixed systems when the H/F ratio is higher than 50/50. Nevertheless, for higher contents of fluorinated gelemulsion in the mixture, the diffusion coefficient increases quickly. The diffusion coefficient of MA in the fluorinated system is much smaller than that in the other compositions studied. The diffusion coefficient of MA in solution obtained by the Taylor dispersion method is 8 × 10-10 m2/s.25 The high MA diffusion coefficient obtained for the H/F ) 10/90 mixture can be attributed to convection, as the gel-emulsion becomes fluid when it breaks, and the process of partitioning the diffusion box may induce some movement in the fluid system, modifying the MA concentration in the compartments. Discussion From the mutual insolubility of hydrocarbons and fluorocarbons one might expect that a mixed highly concentrated emulsion would not form or, if prepared by mixing two highly concentrated emulsions, would be very unstable. However, mixed systems with relatively good stability (about 1 week) could be prepared. This is probably related to the fact that the surfactants constitute a mixture with incompatible hydrophobic tails that are compatible with each oil homologue and polar head groups mutually compatible. The exact structure of the mixed gel-emulsions is not known yet. Whether the interfacial films are formed by a mixture of the surfactants or there exist separate domains formed with each oil-surfactant

couple cannot be deduced from the stability and diffusion results presently available. However, new experiments are currently being performed to elucidate this fundamental question. This information could help in the interpretation of the observed stabilities and in a detailed picture of the diffusion mechanism. The observed decrease in the gel-emulsion stability of the mixtures with respect to that of the fluorinated gelemulsion is probably related to the incompatibility of hydrocarbon and fluorocarbon. Moreover, the evolution of mixed gel-emulsions seems to be qualitatively different from the evolution of hydrogenated and fluorinated systems. Although no macroscopic difference can be observed, the mixed systems are probably more heterogeneous, as suggested by the conductivity measurements (Figure 2). The conductivity of mixed systems increased faster than that of the hydrogenated and fluorinated systems. It can be seen that, in either or both diffusion methods, the flux for the hydrogenated gel-emulsion is much higher than that for the fluorinated one while the mixtures show an intermediate behavior. The accumulation of experiments shows a good reproducibility for both systems. In method I, the comparison of the experimental results with theoretical results based on Fick’s second law shows that this is a good model for the process under study in fluorinated or hydrogenated systems (Figure 3a and e). This would mean that the release from a gel-emulsion to the receptor solution agrees with the imposed conditions: that is, perfect and instantaneous homogeneity of the concentration in the receptor solution and total absence of convective transport within the gel-emulsion. This is in contrast with the behavior of the mixtures where the model cannot fit the experimental curves. Theoretical curves can fit the experiment up to a maximum time that depends on the mixing ratio. To fit the points at higher times, an apparent higher diffusion coefficient has to be used. These two theoretical curves can be observed in Figure 4 for a H/F ) 50/50 gel-emulsion mixture. Therefore it could be considered that the diffusion is accelerated with time. What is obtained is a release curve in which the flux is nearly constant until all the drug has been released. This would be similar to a zero-order release kinetics. This acceleration of the release can be due to the enhanced unstability of the mixed systems as compared with the fluorinated systems. The formation of larger water domains can allow for convection within the emulsion and therefore allows for a faster concentration equilibration. Although there is some dispersion of the data, one can say that the diffusion coefficients at long times are rather constant for the mixtures with an intermediate value (Table 1). Concerning the diffusion in the gel-emulsion itself (method II), solution of Fick’s equation was found to be a good model for all gel-emulsions studied: that is, for the hydrogenated, the fluorinated, and the mixed gelemulsions. Nevertheless, the diffusion time had to be adjusted for each system. Too long a diffusion time would not accomplish the boundary conditions and further could produce higher diffusion coefficients than expected due to the influence of the unstability of the gel-emulsions. On the other hand, too short diffusion times would not allow MA to diffuse enough to produce a concentration profile suitable for an accurate calculation of the diffusion coefficient. Therefore, the fluorinated gel-emulsion was allowed to evolve for a periode of about 20 h (approximately 72 000 s) while the hydrogenated system and the mixed gel-emulsions needed less time (about 15 h, approximately 54 000 s).

Hydrogenated and Fluorinated Gel-Emulsion Mixtures

MA’s affinity for the fluorinated microemulsion is lower than that for the hydrogenated one. This is clearly shown by the values of the partition coefficients. The partition coefficient for the hydrogenated system is around 2.4 while that for the fluorinated one is 0.7 (partition coefficients obtained from quantitative NMR analysis31). For hydrogenated gel-emulsions it was found earlier26 that one of the factors governing the release was the partition coefficient of the marker molecule between the continuous and the dispersed phases of the gel-emulsion. This shows not only that the concentration of releasing molecule will be higher in the continuous phase of the hydrogenated systems but also that a fluorinated film is more effective as a barrier for the release. The differences in release must be a combination of both factors. Conclusion Highly concentrated w/o emulsions (gel-emulsions) have been prepared with mixtures of hydrogenated and fluorinated compounds. Diffusion of a hydrophilic molecule (mandelic acid) has been measured within these gel-emulsions, as well as in hydrogenated and fluorinated gel-emulsions, and to a receptor solution. The model proposed for the release to a receptor solution was found to be adequate for the hydrogenated and fluorinated (31) Ste´be´, M. J.; Rocca, S. Unpublished results.

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systems. The theoretical release curves are obtained by numerical solution of Fick’s first law. The release from mixed systems deviates from this model. The release curves in this latter case are closer to a zero-order kinetic release than those for the hydrogenated and fluorinated systems. This deviation from the model can be attributed to the enhanced instability of the mixtures compared with those of the hydrogenated and fluorinated systems. The model proposed for the diffusion coefficient determination within the gel-emulsion itself was found to fit well all the gel-emulsions studied. The theoretical release curves were obtained by analytical solution of Fick’s second law under determinate boundary conditions. Mixed gelemulsions could be good candidates for releasing drugs at a near constant flux. The control of the stability of the emulsions could lead to a better control of the release. Acknowledgment. The HPLC analysis was performed at the Serveis Cientı´fico-Te`cnics of the Universitat de Barcelona, to which the authors are grateful. Financial support from CICYT (grant QUI96-0454) and from Generalitat de Catalunya (1995SGR-00498) and the CNRS/ CSIC bilateral program (project no. 1933) is gratefully acknowledged. G.C. acknowledges CIRIT for financial support. LA970659R