Growing interest in microemulsions



Recently there is a growing interest in microemulsions due to their drug carrying ability. Microemulsions are known to increase the efficacy of drugs by improving their sustainability and controllability of action hence making them more target oriented without modifying the structure of medicinal compound. Piroxicam is useful in the treatment of rheumatoid arthritis, osteoarthritis and traumatic contusions with gastrointestinal side effects. It is possible to solve these problems by introducing drug carriers which may improve the administration of drug with minimization of side effects due to control of drug release mechanism .

Microemulsions have well known properties and are extensively reported in literature e.g.optically isotropic, transparent and thermodynamically stable homogeneous solutions of oil and water, stabilized by addition of a  a cosurfactant. Oil in water microemulsions can be used for the topical application of drugs due to (a) their high solubilization capacity as well as their favourable thermodynamic interaction with skin which make them more active towards skin (b) favourable partitioning topically (c) reduction of diffusional barrier by o/w microemulsion.

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Extensive physicochemical characterization of an emulsion is essential before it can be made ready to be used for application in pharmaceutical industry. Pharmaceutical application require use of biocompatible ingredients which may not cause any type of toxic effect while interaction with a human body. The microemulsion must be stable while applied in the physiochemical conditions . The microemulsion while loaded must be stable and this can be confirmed by suitable characterization of ME; with and without the loading of medicinal compound. The microstructural changes are of great importance in this regard and physicochemical conditions must be satisfied for successful usage of ME Different techniques such as conductivity, viscosity, density, surface tension and the fluorescence probe studies are useful for monitoring these changes. The release of drug depends on the type of ME and the mechanism of release followed which depends on the type of ME and drug e.g release will be faster for a hydrophilic drug in case of o/w microemulsion.

In this work,  a microemulsion system is constructed for poorly water soluble non-steroidal anti-inflammatory drug piroxicam, comprising of castor oil, a non-ionic surfactant Tween 80, a cosurfactant (ethanol) and phosphate buffer (PB) of pH 7.4. The pseudo-ternary phase diagram has been constructed for this particular system at a constant surfactant to cosurfactant ratio (1:2). Castor oil has a hydroxyl group in addition to unsaturation, making it more polar and its ethoxylates are commonly used as emulsifiers in many applications. Polyoxyethylene fatty acid, stearic acid, oleic acid are used in emulsifiers in oil/water type creams and lotions. Castor oil shows anti-inflammatory effects due one of its major component called ricinoleic acid . Conductivity, viscosity and surface tension are employed to investigate the gradual changes occurring in the microstructure of microemulsion. It is expected that the use of microemulsion formulation may improve the solubility of piroxicam and avoid its degradation.

Materials and Methods


Tween 80 (polyoxyethylene sorbitan monooleate), absolute ethanol (99.8 ≥ %) and castor oil were purchased from Fluka. Pyrene (98 %) was purchased from Sigma-Aldrich. Piroxicam was generously provided by “Amson Vaccines & Pharma (PVT) Ltd” and used without further purification. Phosphate buffer (0.01 M, pH 7.4) was used as the aqueous phase. Buffers were prepared using NaH2PO4/Na2HPO4. 0.1M NaOH and HCl were used to maintain the pH of the solution.


Microemulsion Preparation

The pseudo-ternary phase diagram was delineated (as shown in Fig. 1) using oicastor oil, surfactant (Tween 80; HLB = 15), cosurfactant (ethanol) and aqueous phase PB (pH 7.4) at 25±0.01 ◦C with constant surfactant to cosurfactant ratio (1:2 by mass). The temperature was    maintained at 25±0.01 ◦C using a Lauda M-20 thermostat. Initially castor oil was added to Tween 80/ethanol mixture and the PB was added dropwise to obtain the desired microemulsion compositions. Transparent, single-phase mixtures were designated as microemulsions. All the samples were stable for over 10 months, remaining clear and transparent.

Table 1: Selected microemulsion formulations (%, w/w)









* ME

Castor Oil

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Tween 80




















*Selected Microemulsion (ME) for further analysis

Drug incorporation in Microemulsion

A set of microemulsions, as given in the table1, differing from each other  in weight fractions (Fw) were selected from the single-phase region as given in Fig. 2 to study their physicochemical properties. All of them were stable over 10 months and didn't shown any signs of phase seperation. A 1% w/w composition of Piroxicam was prepared by dissolvingthe it into pre-weight oil component of the systemunder stirring followed by addition of remaining components.

Microemulsion Characterization

Optical Transparency

Polarimetry and visual examination were used to examine the optical transparency of the pure drug loaded microemulsion. The model of the Polarmeter instrument for this purpose was ATAGO, AP-100 Automatic Polarimeter. All these examinations were performed at the room temperature.Centrifugation

Drug Loaded and pure samples of ME were centrifuged at 5500 rpm to check their thermodynamic stability.Each sample was centrifuged at 5500 rpm for 20 min using (Hermle Z200) centrifuge.

Surface Tension

A torsion balance (White Elec. Inst. Co. Ltd.) was used to measure the surface tension at 25 ±0.01◦C under atmospheric pressureThe circumference of the ring for the measurement was 4.0cm. An experimental error of ±0.05 mNm-1 was estimated.

Density and Specific Gravity

Densities and Specific Gravity of pure and drug loaded microemulsion samples were measured by using an Anton Paar (Model DMA 5000) density meter at 25 ±0.01 ◦C. Caliberated density meter was used for performing the measurements. Density of air and pure water are used as standards for caliberation.

Refractive Index

The refractive indices of the samples were experimentally determined using a refractometer (ATAGO, RX-5000) by placing a drop of solution on the slide.


The pH of all the selected pure ME samples and the drug loaded ME was determined at room temperature using a pH Meter (WTW 82362 Weilheim) fitted with a pH electrode (WTW A061414035). The temperature was kept constant (25±0.01 ◦C) using a Lauda M-20 thermostat.

Conductivity Measurements

Electrical conductivity is a suitable tool for the measurement of the effect of the amount of water phase of microemulsion. Microprocessor Conductivity Meter (WTW 82362 Weilheim) fitted with an electrode (WTW 06140418) having a cell constant of 1.0 cm-1 was used for the purpose of measurement of conductivity (σ). Conductivity measurements were carried out by titration of oil and surfactant/cosurfactant mixture with buffer (along the dilution line AB in Fig. 1). The conductivity of selected and drug loaded microemulsions was also measured. The error limit of conductance measurements was ±0.02 μscm-1.

Viscosity Measurements

Viscosities were measured with calibrated Ubbelhode viscometer at 25±0.1 ◦C. For each measurement, the viscometer was washed, rinsed and vacuum dried. To follow the viscous behaviour of the microemulsions, flow time was measured for all the selected and drug-loaded microemulsions (1 wt% drug). The error limit of viscosities measurements was ±3%.

Results and Discussion

Castor oil, a fatty acid, known for its high permeability, was used to prepare ME system [18-20]. A non-ionic surfactant, tween-80 is used due to its abundant usage in commercial formulations of pharmaceutical due to its non-toxic nature [21-23] where ethanol was used a co-surfactant so that there is no need for any input of additional energy and make the so formed composition ready as a potential drug carrier system.. [24-26]. Before the addition of aqueous phase, a so called oily phase comprising only of surfactant, oil, and ethanol exists. Ethanol affects its critical packing parameter (CPP) of tween 80 as cited in literature and is known to suppress the formation of unwanted phases. When water is gradually added to the so called oily phase, it favors the organization of the head groups of the tween 80 into a polar core while the fatty acid tails are oriented such that they are present in the oil continuous phase.

Phase Studies

Tween-80/ethanol/castor oil/buffer at 25 ◦C.

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Phase behavior investigations of this system demonstrated the suitable approach to determining the water phase, oil phase, surfactant concentration, and cosurfactant concentration with which the transparent, 1-phase low-viscous microemulsion system was formed. The phase behavior exhibits a two-phase region, a three-phase region and a large single-phase region which gradually and continuously transformed from buffer rich side of binary solution (buffer/surfactant micellar phase) of pseudo-ternary phase diagram towards the oil rich region. This laid an emphasis on a continuous transition from water rich compositions to oil swollen micelles.

The phase study revealed that the maximum proportion of oil was incorporated in microemulsion systems when the surfactant-to-cosurfactant ratio was 1:2. From a formulation viewpoint, the increased oil content in microemulsions may provide a greater opportunity for the solubilization of piroxicam. Eight microemulsions (1-8) were selected from the single-phase isotropic region (Fig. 2), with compositions mentioned in Table 1. Selected Microemulsion (ME) was further analyzed by conductivity, viscosity, density, surface tension, refractive index and pH. The values of measured parameters have been presented in Table 2.

Table 2: Physical Parameters of Selected Microemulsion (ME) & after Incorporation of Drug

Physical Property

S:CoS = 1:2


(no drug)


(drug loaded)

Refractive Index



Conductivity  (μs/cm)



Kinematic Viscosity (cPLg-1)



Density (gL-1)



Viscosity (cP)



Surface Tension (mN/m)



Specific Gravity






Conductivity Measurements

Conductometry is a useful tool to assess microemulsion structure. Conductivity studies have elucidated the existence of a characteristic zone with an isotropic microemulsion domain in a continuum. Electric conductivity (s) was measured as a function of weight fraction of aqueous component Fw (% wt) for the oil, surfactant/cosurfactant mixture along the dilution line AB (shown in Fig. 2). The results of variation of s vs Fw (% wt) are shown in Fig. 3 (a). The behavior exhibits profile characteristic of percolative conductivity . The conductivity is initially low in an oil-surfactant mixture but increases with increase in aqueous phase.

While the water volume fraction increases, the electrical conductivity of the system slightly increases as well until the critical Fw is reached when a sudden increase in conductivity is observed. This phenomenon is known as percolation, and the critical Fw at which it occurs is known as percolation threshold Fp.

The value of conductivity below Fp suggests that the reverse droplets are discrete (forming w/o microemulsion) and have little interaction. Above Fp the value of s increases linearly and steeply till it touches the value of Kb. The interaction between the aqueous domains becomes progressively more important and forms a network of conductive channel (bicontinuous microemulsion) [30]. Beyond the percolation threshold (Fp ≈ 6%) conductivity increases linearly and sharply up to (Fw ≈ 20%). It can be concluded that beyond Fp a network of conductive channels exists, which corresponds to the formation of water cylinders or channels in an oil phase due to the attractive interactions between the spherical micro-droplets of water phase in the w/o microemulsion. With further increase in water content, above Fb (Fw > 20%), the s shows a sharp decrease, which may be due to strong attractive forces as system becomes more viscous [15, 30]. Fig. 3 (b) depicts the variation of log s vs weight fraction of water (Fw). The change in the slope of log s can be interpreted, as a structural transition to bicontinuous from w/o , nearly at Fw = 6%. The transition takes place once the aqueous phase becomes continuous phase i.e. at Fb. This is in line with the observation made in phase study. Thus, the s vs Fw plot illustrates occurrence of three different structures (namely w/o, bicontinuous, o/w). The conductivity of the microemulsions containing more than 20 wt% water decreased significantly, probably due to the higher viscosity.

The percolation threshold can be determined from the plot (ds/dFw), as a function of the water weight fraction, Fw (% wt) . A maximum in the first derivative of conductance Fw at ~12wt % water is observed (Fig. 4) confirming the presence of percolation behavior (bicontinuous microstructure) in this region [31]. The electric conductivity of pure selected and drug loaded microemulsion (1.0%) is given in Table 2. A comparison of two systems shows that drug incorporation does not affect the microstructure of the microemulsion.

Viscosity Measurements

To avoid the ambiguity of probably non-Newtonian flow behavior of microemulsion the flow time has been used as an index of viscosity . Flow time of oil, surfactant/cosurfactant mixture along the dilution line AB (shown in Fig. 2), was measured as a function of weight fraction of water Fw(wt %) and is shown in Fig. 5. Similar trend has been observed for the viscosity of oil, surfactant/cosurfactant mixture as a function of Fw(Fig. 6). The rapid change in the viscosity is probably due to the change in the microstructure of the microemulsion. The change in the internal structure could be due to either the change in the shape of droplets or may be due to the transition from w/o to bicontinuous microemulsion. It is well known that increase of volume fraction of dispersed phase in microemulsion increases viscosity of the system .

For the system studied viscosity increases with increase in Fw(wt% of aqueous phase). Difference in the viscosities is more profound for lower water content values in comparison to the dilute system. The microemulsion system is turning to be more viscous with addition of water and thus may help in the slow diffusing of drug at infinite dilution. The microemulsion system thus, shows a structural change from oil continuous system to water continuous, which has higher viscosities than the former . The plots of hk (kinematic viscosity), d2η/d2Fw and 1/η dη/dFw versus Fwreflect that the transition occurs at ~11% weight fraction of aqueous phase (Fig. 6). The transition point of surface tension, conductivity and viscosity plots coincides well at ~11% weight fraction of aqueous phase and confirms the presence of percolative behavior.

Surface Tension

The surface tension increases linearly over the same range of water content (Fig. 7), but two breaks (at ~7.0 and ~20 wt% water) suggest that structure changes occur at these compositions. The surface tension measurements showed increment, when measured as a function of weight fraction of aqueous component, expect for the ~12% weight fraction where the value suddenly decreased and thereafter a regular increase was observed. This low surface tension value showed the presence of bicontinuous microemulsion between oil and water rich system, which is because of presence of self-assembled organize microstructure in it [13, 35,]. The results coincide well with the electric conductivity and viscosity measurements. It can be assumed that the added alcohol (ethanol) is incorporated in the interfacial structure in such a way that more water is on the outside of the “oil drops”, causing the increase in surface tension. Incorporation of drug showed a negligible change in the surface tension measurements, therefore indicting the possibility of piroxicam molecules into the palisade layer on the inner side of microemulsion.


A pseudo-ternary phase diagram was successfully constructed for the system under investigation i.e., Tween 80/ethanol/castor oil/buffer. The conductivity and viscosity studies along the dilution line (in phase diagram) depict the Structural transition from w/o to o/w via bicontinuous phase at ~11% Φw (wt% fraction of aqueous phase) was supported by conductivity and viscosity data. Among the selected microemulsions (I-VIII), MEX was found to be best possible, stable and optically clear, composition for the incorporation of piroxicam The surface tension and fluorescence studies indicated that the drug may reside at the interface of oil and aqueous phase. The ME system was successfully applied to increase the solubilization of drug.