Interfacial Modification and Structural Transitions Induced by Guest Molecules Solubilized in U‐Type Nonionic Microemulsions

Abstract

Alcohols and polyols are essential components (in addition to the surfactant, water, and oil) in the formation of U‐type self‐assembled nano‐structures, (sometimes called L‐phases or U‐type microemulsions). These microemulsions are characterized by large isotropic regions ranging from the oil side of the phase diagram up to the aqueous corner. The isotropic oily solutions of reverse micelles (“the concentrates”) can be diluted along some dilution lines with aqueous phase to the “direct micelles” corner via a bicontinuous mesophases (i.e., two structural transitions). This dilution takes place with no phase separations or occurrence of liquid crystalline phases. The structural transitions were determined by viscosity, conductivity, and pulsed gradient spin echo NMR (PGSE NMR), and are not visible to the eye. Two guest nutraceutical molecules (lutein and phytosterols) were solubilized, at their maximum solubilization capacity, in the reversed micellar solutions (L₂ phase) and were further diluted with the aqueous phase to the aqueous micellar corner (L₁ phase). Structural transitions (for the two types of molecule) from water‐in‐oil to bicontinuous microstructures were induced by the guest molecules. The transitions occurred at an earlier stage of dilution, at a lower water content (20 wt.% aqueous phase), than in the empty (blank) microemulsions (transitions at 30 wt.% aqueous phase). The transitions from the bicontinuous microstructure to the oil‐in‐water microemulsions were retarded by the solubilizates and occurred at later dilution stage at higher aqueous phase contents (50 wt.% aqueous region for empty microemulsion and >60 wt.% for solubilized microemulsion). As a result, the bicontinuous isotropic region, in the presence of the guest molecules, becomes much broader. It seems that the main reason for such “guest‐induced structural transitions” is related to a significant flattening and enhanced rigidity of the interface. The guest molecules of the high molecular volume are occupying high volume fraction of the interface (when the solubilization is maximal).     

Viability and permeability across Caco-2 cells of CBZ solubilized in fully dilutable microemulsions

The purpose of this study was to evaluate the viability and permeability of carbamazepine (CBZ) solubilized in fully dilutable non-ionic microemulsions across Caco-2 cells used as a model for intestinal epithelium. Maximum solubilization capacity (SC) of CBZ was determined within water-in-oil (W/O), bicontinuous and oil-in-water (O/W) structures formed upon dilution. The effect of the nature of the oil phase, surfactant type, and the ratio between the oil phase and surfactant on the quantity of solubilized CBZ, droplets size, the viability of the cells and drug permeability was elucidated. We found that: (1) several fully dilutable microemulsions based on pharma-grade ingredients can be loaded with very significant amounts of CBZ, (2) W/O microemulsions (10wt% water) exhibit up to 3-fold higher solubilization capacity over the drug's solubility in oil (triacetin), (3) CBZ in the O/W microemulsions (80wt% water) exhibit up to 29-fold higher solubilization than in water, (4) the O/W droplets of the examined systems are 9-11nm in size, (5) the highest permeability was obtained in systems containing triacetin/alpha-tocopherol acetate/ethanol in 3/1/4wt% ratio as oil phase and Tween 60 as surfactant, (6) the replacement of alpha-tocopherol acetate by alpha-tocopherol inhibits CBZ release, (7) replacement of a saturated chain of Tween 60 by an unsaturated (Tween 80) or shorter chain (Tween 40) inhibited drug release, (8) the decrease in the oil phase to surfactant ratio leads to enhancement of drug release (dilution line 64>dilution line 73).     

Improved solubilization of Celecoxib in U-type nonionic microemulsions and their structural transitions with progressive aqueous dilution

Celecoxib (clxb) is an important drug for treatment of rheumatoid arthritis and osteoarthritis by specifically inhibiting the enzyme cyclooxygenase-2 (COX-2). Clxb is a type 2 drug characterized by low water solubility (<5 mug/ml) and fast transmembrane transport. The present formulations require high dosage since the transmembrane transport fluctuates and is very difficult to control. Dissolving the drug within an oil phase was not practical since its dissolution was very small and its dispersion in water was impossible. In our recent studies, we learned to construct U-type phase diagrams and to formulate reverse microemulsions (oil-based concentrates) that are progressively and fully dilutable with aqueous phase. In the present study, we solubilized clxb in nanostructures of reverse micelles of U-type nonionic microemulsions that consisted of R(+)-limonene, alcohol, propylene glycol (PG), and hydrophilic surfactant (Tween 60). The solubilization capacity of the drug in these systems is many times higher than in either the oil or the aqueous phase. The clxb solubilized microemulsions are fully diluted with aqueous phase without phase separation. The solubilization capacity decreases as the water content increases. Electrical conductivity, viscosity, and self-diffusion (SD) coefficients of the microemulsion components were measured along a suitable water dilution line. The three major microemulsion regions were detected and the transitions between the W/O to bicontinuous phase and from this phase to the O/W droplets were identified (at 30 and 70 wt% aqueous phase, respectively). From the SD coefficients, it was found that the drug is initially solubilized at the interface of the W/O droplets and there are no significant structural changes. The transition to a bicontinuous phase occurs at the same water content as in the empty (i.e., without drug) system. From the viscosity profiles, we concluded that the drug affects the structure of the bicontinuous phase as reflected in the water content at which the oil-continuous network is destroyed and full inversion occurs (50 vs 55 wt% in the drug-loaded system). Upon further dilution the drug remains solubilized at the interface and is oriented with its hydrophilic part facing the water, and is strongly affects the inversion to O/W droplets. From Small Angle X-ray Scattering (SAXS) measurements we learned that the drug effects the structure of microemulsion droplets and forms "ill-defined structures," probably less spherical. Yet, the overall droplet sizes at the high dilutions did not change very much.     

Competitive solubilization of cholesterol and phytosterols in nonionic microemulsions

It is well documented that phytosterols inhibit the uptake of exogenic cholesterol and do not interfere with cholesterol synthesis or cause side effects. The mechanism by which phytosterols interfere with cholesterol absorption is not completely clear and there are at least three hypotheses for their beneficial activity. Among these is that of competitive solubilization of phytosterols and cholesterol in dietary mixed micelles. In the present study we investigated the competitive solubilization of phytosterols (approximately 50% beta-sitosterol) and cholesterol in a nonionic microemulsion system constructed as a model for the dietary mixed micelles. We studied the effect of the competitive solubilization of cholesterol and phytosterols on the structural transformations and physical properties of the microemulsion and evaluated the locus of the solubilizates within the nanodroplets of each sterol separately and when they are loaded together at different weight ratios along one dilution line. Our results show that chemical and structural differences between cholesterol and phytosterols significantly influence the solubilization capacity of the nonionic microemulsion. Cholesterol, being more amphiphilic, is solubilized more efficiently at the W/O microemulsion interface, while in the O/W microemulsion phytosterols are dissolved somewhat more efficiently in the droplet core.     

Solubilization of Celecoxib in Microemulsions Based on Mixed Nonionic Surfactants and Peppermint Oil

U-type microemulsions formulated with water, mixed nonionic surfactants, and peppermint oil were used to solubilize celecoxib. Microemulsion dilution and interfacial factors contributing to the celecoxib solubilization were evaluated. Celecoxib solubilization capacity decreases with the increase in the water content. Electrical conductivity, dynamic viscosity, and SAXS measurements reveal the structural transition occurring in the microemulsion region. It was found that below 0.25 aqueous phase volume fraction the water-in-oil microemulsions are present, the transition between the water-in-oil to bicontinuous and then to oil-in water microemulsions occur at 0.30 and 0.8 aqueous phase volume fraction, respectively. The results demonstrate that the solubilized drug affects the transition from bicontinuous to water-in-oil microemulsions. The solubilized drug increases the hydrodynamic radius of the oil-in-water microemulsion droplets measured by dynamic light scattering.     

Improved solubilization of carbamazepine and structural transitions in nonionic microemulsions upon aqueous phase dilution

Solubilization capacity and structural transformations in nonionic microemulsions characterized by a large continuous isotropic region forming dilutable self-assembled nanodroplets containing solubilized carbamazepine, were studied along dilution lines 73 and 82 (70 and 80 wt% surfactant and 30 and 20 wt% of oil phase, respectively). The preparations were based on pharma-grade ingredients, water, R-(+)-limonene, ethanol, propylene glycol, and Tween 60. Solubilization capacity (SC) of the drug was dependent on the microstructure of the microemulsion and on the surfactant-to-oil phase weight ratio. The SC in the concentrate (reversed micelles) was 15 times higher than its solubility in the oil. Transition of the W/O microemulsion to a bicontinuous phase and to O/W droplets were indentified by electrical conductivity, viscosity, SAXS, and SD-NMR measurements. Once the system is diluted to 90 wt% aqueous phase, the SC is 10 and 16-fold higher, along dilution lines 73 and 82, respectively, than in pure water. Being solubilized, carbamazepine serves as a cosurfactant therefore it affects the curvatures of the microstructures and consequently the boundaries of the structural regions and the transition points between the different phases. Dilutable microemulsions are promising new carbamazepine vehicles for oral intake.     

SYNERGETIC EFFECT OF SUCROSE AND ETHANOL ON FORMATION OF TRIGLYCERIDE MICROEMULSIONS

The phase behavior of soybean oil, a nonionic surfactant (ethoxylated monodiglycerides) and an aqueous phase of water containing ethanol, and sucrose was investigated at 35 and 40°C. A minimum concentration of 20 wt% ethanol was required for the formation of isotropic solutions. Addition of sucrose to the aqueous phase decreased the amount of ethanol required to form these solutions. The solubilization mechanism of the oil was investigated by small angle x-ray diffraction and polarized light microscopy. A stable lamellar liquid crystalline phase was formed for a mixture of 75/25 surfactant/sucrose solution (2.5 wt% sucrose). This phase was destabilized with increased concentrations of sucrose and liquid crystalline phases having hexagonal structures were favored at 8.75 wt% sucrose. At a ratio of 55/45 wt% of surfactant/sucrose solution (9 wt% sucrose) hexagonal structures were formed and could be destabilized or destroyed by addition of ethanol. The concept of stabilization and destabilization of liquid crystalline mesophases was applied to the solubilization of triglycerides in aqueous solutions. Two microemulsion regions were identified; oil-in-water (L₁) and water-in-oil (L₂) in systems containing soybean oil, ethoxylated monodiglycerides, and 20 wt% ethanol solution. At 55/45 wt% surfactant/20 wt% ethanol solution,7.5 wt% of soybean oil was solubilized. Addition of 10, 20, and 30 wt% sucrose, at the same ratio of surfactant to ethanol solution, increased the solubility of the oil to 9, 13.5, and 18 wt% respectively. In addition, the size of the L₁ phase increased and moved to the aqueous corner of the phase diagram and the size of the L₂ phase decreased.     

Water Solubilization in Nonionic Microemulsions Stabilized by Grafted Siliconic Emulsifiers

Microemulsions containing octanol, decanol, or dodecanol as the oil phase and oligomeric, grafted nonionic amphiphiles based on ethoxylated polymethylsiloxanes (Silwets) have been studied. It was demonstrated that significant amounts of water can be solubilized only when the hydrophobic siliconic backbone is very short (trimers). The water solubilization was evaluated using SAXS, DSC, and conductivity measurements. It was found that up to 40 wt% of water can be solubilized in dodecanol and Silwet L-7607 (MW 1000 and 75 wt% ethylene oxide (EO)). Surprisingly, no free water was detected in the aggregate core. All the solubilized water was confined in the vicinity of the interphasal region and froze at -10 degrees C and below. Up to three molecules of water can be associated with each EO headgroup. Based on SAXS measurements, the structural units of the microemulsions were interpreted to be lamellar-like, a form previously found for the related monomeric microemulsions. Copyright 2001 Academic Press.     

Diclofenac Solubilization in Microemulsions Based on Mixed Nonionic Surfactants and R (+)-limonene

Diclofenac is a nonsteroidal anti-inflammatory drug that reduces inflammation and pain hormones in the body. Dispersing the drug in water is impossible and its solubility in oils is very limited. In this study, we solubilized sodium diclofenac in nanostructures of the constructed U-type water/sucrose laurate/ethoxylated mono-di-glyceride/oleic phase microemulsions. The mixing ratio (w/w) of sucrose laurate/ethoxylated mono-di-glyceride equals unity. The oleic phase was the pure R (+)-limonene or R (+)-limonene mixed with ethanol at a weight ratio equals unity. The solubilization capacity of the drug in these systems is many times higher than in either oil or water systems. The sodium diclofenac solubilized microemulsions are fully diluted with water without phase separation. The solubilization capacity decreases as the water content increases. The system free of alcohol solubilizes less amounts of drug over all the range of water contents compared to the system containing alcohol. Small angle x-ray scattering was used to evaluate the effect of solubilized sodium diclofenac on the microstructure and diffusion properties of the loaded microemulsions. From the periodicity and correlation length measured by small angle x-ray scattering, we learned that the drug affects the structure of loaded microemulsion droplets probably less spherical than the empty systems. The transition from water-in-oil to a bicontinuous phase occurs at the different water contents compared to the empty (i.e., without drug) microemulsions. The drug remains solubilized at the interface upon further dilution with water and is oriented with its hydrophilic part facing the water, and strongly affects the inversion to oil-in-water droplets.     

Phase transition induced bywater dilution in phospholipid U-type food-grade microemulsions studied by DSC

In this study we used differential scanning calorimetry to clarify the role of water activity within the nano-droplets, and to explore phase transitions in novel phospholipids based fully dilutable food-grade microemulsions. The microstructure transitions were investigated along two water dilution lines (50:50 and 80:20 mass% surfactant mixture/oil phase). From the water thermal behavior we learned that three structural regions can be identified along the water dilution lines. The thermal transition points coincide with the structural phase transition of the microemulsions as measured by other methods (electrical conductivity and SD-NMR measurements). The structural transitions were detected at 20 and 45 mass% of water along dilution line 55, where along dilution line 82 it occurs at 40 and 50 mass% of water. The microemulsions along dilution line 82 seem to have more compact surfactant packing film, thus the film has stronger resistance to transformation upon dilution, resulting in a smaller bicontinuous region than the one formed at dilution line 55. The difference in phase transition point can be used for triggering the release of future solubilizate.     

Oil-Induced Structural Change in Nonionic Microemulsions

Effect of added oil (heptane or squalane) on the microemulsion structures in polyoxyethylene dodecyl ether (C₁₂EO_n) systems was investigated by means of phase behavior and NMR diffusion experiments. In the binary water-C₁₂EO_n systems, an isotropic fluid, D₂ (or L₃), and an aqueous micellar solution, Wm, phases are successively formed with increasing the EO-chain length. Upon addition of heptane, D₂ and Wm phases are merged and a microemulsion of large solubilization is produced at a low surfactant concentration. With squalane, the solubilization of oil in D₂ phase is very low or almost zero, whereas the oil solubilization in Wm phase is relatively large. These structural changes in microemulsions are discussed based on the self-diffusion coefficients of water, oil, and surfactant measured by the PGSE-NMR method. The difference in the phase behavior may be attributed to the difference in the penetration tendency of oil in the surfactant palisade layer.     

Characterization of cephalexin loaded nonionic microemulsions

Water/propylene glycol/sucrose laurate/ethoxylated mono-di-glyceride/isopropyl myristate/peppermint oil U-type microemulsions were used to solubilize cephalexin. Microemulsion dilution and interfacial factors contributing to the cephalexin solubilization were evaluated. Cephalexin solubilization capacity increases with the increase in the aqueous phase volume fraction (φ) up to 0.4 then decreases. Electrical conductivity of drug loaded and drug free microemulsions increases with φ. The hydrodynamic radius measured by dynamic light scattering of the oil-in-water loaded microemulsions decreases with temperature. The microemulsions were characterized by the volumetric parameters, density, excess volume, ultrasonic velocity and isentropic compressibility. The microemulsion densities increase with φ up to 0.8 then decrease. The excess volume decreases with φ up to 0.8 then stabilizes. Ultrasonic velocities increase with the increase in φ while isentropic compressibility decreases. Analysis of the volumetric parameters enabled the characterization of structural transition along the microemulsion phase region. The presence of water-in-oil, bicontinuous and oil-in-water microemulsions, at aqueous phase volume fractions below 0.2, between 0.3 and 0.7 and above 0.8, respectively were found. Interfacial properties and dynamic structure of the monolayer for drug loaded and drug free microemulsions, were studied by electron paramagnetic resonance spectroscopy employing the nitroxide spin probe 5-doxylstearic acid. The rigidity of the interface was affected by the water content and also the presence of cephalexin.     

Structural changes in poly(ethyleneimine) modified microemulsion

The influence of branched poly(ethyleneimine) on the phase behavior of the system sodium dodecylsulfate/toluene-pentanol (1:1)/water has been studied. The isotropic microemulsions still exist when water is replaced with aqueous solutions of PEI (up to 30% in weight), but their stability is significantly influenced. From a polymer concentration of 20 wt%, the polymer enhances the solubilization of water in oil, changes the sign of the spontaneous curvature of the surfactant film, and induces an inversion of the microemulsion type from water-in-oil (L(2)) to oil-in-water (L(1)), by the formation of a bicontinuous channel. Further investigations show that the addition of polymer in the L(2) phase changes the droplet-droplet interactions as the conductivity drops and the percolation disappears. In the bicontinuous channel, higher viscosities can be detected, as well as a weak percolation followed by a steep increase of the conductivity, which can be related to evident structural changes in the system. DSC measurements allow then to follow the changes of the water properties in the system, from interfacial-water in the L(2) phase to free-water in the sponge-like phase. Finally, all the measurements performed permit to characterize the structural transitions in the system and to understand the role of the added polymer.     

Structural transformations in a water-<Emphasis Type="Italic">n</Emphasis>-octane + chloroform-sodium dodecyl sulfate-<Emphasis Type="Italic">n</Emphasis>-pentanol microemulsion

Conductivity, viscosity, and water and oil solubilization are measured, and the parameter of hydrophilic-lipophilic balance is calculated for stable water-n-octane + chloroform-n-pentanol-sodium dodecyl sulfate microemulsions (Winsor Type IV system) at a water content of 2.5–56 vol %. Domains of the most probable existence of globular and bicontinuous structures and the boundaries of the transitions between the following states of the system are determined: reverse micelles containing solubilized water, a water-in-oil microemulsion, a microemulsion with a continuous structure, an oil-in-water microemulsion, and normal micelles containing solubilized oil. Peculiarities of the bicontinuous structure of the microemulsions and the relation between parameter R of the Winsor theory and the parameter of the hydrophilic-lipophilic balance of microemulsion, which the authors have determined, are discussed.     

Effect of ionic surfactants on the phase behavior and structure of sucrose ester/water/oil systems

The phase behavior and structure of sucrose ester/water/oil systems in the presence of long-chain cosurfactant (monolaurin) and small amounts of ionic surfactants was investigated by phase study and small angle X-ray scattering. In a water/sucrose ester/monolaurin/decane system at 27 degrees C, instead of a three-phase microemulsion, lamellar liquid crystals are formed in the dilute region. Unlike other systems in the presence of alcohol as cosurfactant, the HLB composition does not change with dilution, since monolaurin adsorbs almost completely in the interface. The addition of small amounts of ionic surfactant, regardless of the counterion, increases the solubilization of water in W/O microemulsions. The solubilization on oil in O/W microemulsions is not much affected, but structuring is induced and a viscous isotropic phase is formed. At high ionic surfactant concentrations, the single-phase microemulsion disappears and liquid crystals are favored.     

Micellar solubilization of tributylphosphate in aqueous solutions of Pluronic block copolymers. Part I. Effect of the copolymer structure and temperature on the phase behavior

Solubilization of tributylphosphate (TBP), a polar oil, in various micellar solutions of Pluronic has been investigated by turbidimetry emphasizing the effect of temperature and the role of the PPO and PEO blocks on the phase behavior of the three components systems (Pluronic-TBP-water). [Temperature-composition] diagrams allow monophasic and diphasic domains to be delimited. Two temperatures are shown to have a determining effect on the phase behavior (TBP solubilization); the well known cloud point temperature (CPT, here defined for the three components system) and the solubilization minimum temperature (SMT) which is defined as the lowest temperature allowing solubilization of TBP in the system. Both temperature depend on the copolymer structure and, interestingly, are directly related to the TBP concentration in the medium. Monophasic microemulsions are observed when the temperature ranges between the SMT and the CPT. When TCPT the system separates in two phase due to the co-precipitation of TBP and Pluronic. Moreover an unexpected evolution of the CPT with the TBP content clearly indicates the occurrence of a structural change of the microemulsions which allows higher quantities of TBP to be solubilized. But the structural change does not allow alone higher quantities of TBP to be solubilized. A well compromise between the SMT and the CPT must be also observed so as to obtain a large extent of monophasic domain after the restructuration. The best compromise is obtained with Pluronics with intermediate hydrophobic character. Reversely, hydrophobic and hydrophilic Pluronics exhibit a very small extent of monophasic domain after the restructuration which does not allow benefit by the structural change.     

Solubilization of food bioactives within lyotropic liquid crystalline mesophases

Liquid crystals are widely utilized as model systems to mimic biological processes where the phase behavior of lipids plays a mediating role. In various foods and pharmaceutical and biotechnical applications, the liquid crystalline phases formed by surfactants in an aqueous medium represent useful host systems for drugs, amino acids, peptides, proteins and vitamins.Various biologically active food additives are soluble in neither aqueous nor oil phase and require environmental protection against hydrolysis or oxidation. Lyotropic liquid crystals meet these requirements mainly due to their high solubilization capacities for hydrophilic, lipophilic and amphiphilic guest molecules. Moreover, recent studies demonstrated controlled and/or sustained release of solubilized molecules from different liquid crystalline matrices.This paper surveys the solubilization of hydrophilic, lipophilic and amphiphilic guest molecules for food applications and illustrates the corresponding structural transformations. Recent developments in liquid crystal characterization methods are discussed.     

The effect of structure of oil phase, surfactant and co-surfactant on the physicochemical and electrochemical properties of bicontinuous microemulsion

Efforts were made to prepare bicontinuous microemulsions with ten different oil phases involving aliphatic, linear, and aromatic hydrocarbons as oil phases, two co-surfactants (n-butanol and n-pentanol) and two surfactants: cationic (CTAB) and anionic (SDS). Different weight percentages were employed for the preparation of cationic and anionic surfactant based microemulsions as reported in the literature. Out of the 40 compositions (10 oil phasesx2 co-surfactantsx2 surfactants) thus selected only 28 systems showed stable bicontinuous microemulsion phase. This behavior is explained on the basis of the structures of various constituents present in the microemulsions. Viscosity variations of stable bicontinuous microemulsions are found to depend mainly on the nature of co-surfactant. Conductivity behavior on the other hand depends mainly on the weight percentage and composition of aqueous phase. The solubility of pyrene in the oil phase determines the excimer formation and fluorescence behavior in microemulsions. The electron transfer property of both the water-soluble and the oil-soluble redox systems does not depend on the oil phase and the co-surfactant. The significance and importance of characterizing well defined bicontinuous microemulsions is thus highlighted.     

非水反相微乳的加溶与电导性质研究

研究了若干非水极性溶剂（甲酰胺、二甲基亚砜和乙腈）及其与水的混合物/AOT/正庚烷反相微乳体系的加溶性质及其电导行为.结果表明，在AOT反相微乳中，非水极性溶剂的最大加溶量均远小于水的加溶量.其最大加溶量顺序为二甲基亚砜< 甲酰胺< 乙腈< 水.甲酰胺和乙腈与水的加溶相互抵制，而水在一定范围内可促进二甲基亚砜的加溶.非水反相微乳的电导率随加溶量的变化规律与含水反相微乳体系类同，但到达电导率极大值和出现渗滤时的加溶量明显比含水反相微乳 体系的要小.     

Sucrose ester-based biocompatible microemulsions as vehicles for aceclofenac as a model drug: formulation approach using D-optimal mixture design

We assessed the functionality of sucrose esters (sucrose laurate, myristate, palmitate, and stearate), relatively innocuous nonionic surfactants, in formulation of biocompatible microemulsions. The putative influence of surfactant structure on the extension of microemulsion region was explored through the construction of the pseudo-ternary phase diagrams for the isopropyl myristate/sucrose ester-isopropyl alcohol/water system, using the titration method and mixture experimental approach. Minor changes in surfactant tail length strongly affected the microemulsion area boundaries. D-optimal mixture design proved to be highly applicable in detecting the microemulsion regions. Examination of conductivity, rheology, and thermal behavior of the selected sucrose laurate and sucrose myristate-based microemulsions, upon dilution with water, indicated existence of percolation threshold and suggested the phase inversion from water-in-oil to oil-in-water via a bicontinuous structure. Atomic force micrographs confirmed the suggested type of microemulsions and were valuable in further exploring their inner structure. The solubilization capacity of aceclofenac as a model drug has decreased as the water volume fraction in microemulsion increased. High surfactant concentration and the measured solubility of aceclofenac in microemulsion components suggested that the interfacial film may mostly contribute to aceclofenac solubilization.