INTRODUCTION:

Emulsions are heterogeneous system in which one immiscible liquid is dispersed as droplets in another liquid. Such a thermodynamically unstable system is kinetically stabilized by addition of one further component or mixture of components that exhibit emulsifying properties. One emulsion that is further dispersed into another continuous phase is called double emulsion, multiple emulsion or emulsified emulsion. The droplet-size distribution of emulsion droplets is 0.5-50.0μm.

The inner droplet size distribution of w/o emulsion in multiple emulsions is usually smaller than 0.5μm, where as the outer, external multiple emulsions is quite large and can exceed 10μm.

Another emulsion system is “microemulsion” and can define a system of water, oil and amphiphile, which is a single optically isotropic. The droplets in a microemulsion are in the range of 0.1-1.0μm⁽¹⁾. The existence of this theoretical structure was later confirmed by use of various technologies and we can today adopt the definition given by Attwood as follows: “A microemulsion is a system of water, oil and amphiphilic compounds (surfactant and co-surfactant), which is a transparent, single optically isotropic and thermodynamically stable liquid”⁽²⁾.

Microemulsion is homogenous, thermodynamically stable dispersion of water and oil stabi)lized by relatively large amounts of surfactant(s) frequently in combination with cosurfactant(s)^(3-8).

Microemulsion shows diverse structural organization due to the use of wide range of surfactant concentration, water-oil ratios, temperature etc. (Lawrence et al., 2005). In case of emulsion, it contains three components, namely oil, water and surfactant; whereas microemulsions generally require a forth component i.e. cosurfactants, which include linear alcohols of medium chain length that is miscible with water. The combination of surfactant and co-surfactant promotes the generation of extensive interfaces through the spontaneous dispersion of oil in water, or vice-versa. The large interfacial area between oil and water consists of a mixed interfacial film containing both surfactant and cosurfactant molecules. The interfacial tension at the oil-water interfaces in emulsions approaches zero, which also contributes to their spontaneous formation. Microemulsions are regarded as micelles extensively swollen by large amounts of solubilized oil ^(9,10)

Advantage of Microemulsions:^(11-17)

Microemulsions system has considerable potential to act as a drug delivery vehicle by incorporating a wide range of drug molecules.

(1) Good thermodynamically stable and inexpensive.

(2) It is used in the wide range of pharmaceuticals and cosmetics formulation.

(3) It is used as a vehicle for topical, oral, nasal and transdermal applications.

(4) It is used as bioavailability enhancers for poorly water soluble drug.

(5) It acts as a penetration enhancers and 'supersolvents' of drug.

(6) Long shelf life.

(7) Wide applications in colloidal drug delivery systems for the purpose of drug targeting and controlled release

(8) Helpful in taste masking.

Disadvantage of Microemulsions^(18-21)

(1) The main problem in a microemulsions application is a high concentration and a narrow range of physiologically acceptable surfactants and cosurfactants.

(2) It has limit potential topical application due to their toxic and irritant properties of “component.

(3) Large surfactant concentration (10-40%) determines their stability.

(4) It is poor palatability due to the lipid content leading to the poor patient compliance. Moreover due to their water content, Microemulsions cannot be encapsulated in soft gelatin or hard gelatin capsules.

Limitations

Factors which limit the use of microemulsion in pharmaceutical applications.

· The concentration of surfactants and co-surfactants used must be kept low for toxicological reasons.

· Suffers from limitations of phase separation.

· For intravenous use, the demand of toxicity on the formulation is rigorous and very few studies have been reported so far.

Use of those surfactants which are included in “generally regarded as safe” (GRAS) category can reduce toxicity.

Components of microemulsion system:^(22-33)

Oil phase:

The most important excipients in the formulation is the oil phase, not only because it can solubilize the required dose of the lipophilic drug, it can increase the fraction of lipophilic drug transported via the intestinal lymphatic system, thereby increasing absorption from the GI tract depending on the molecular nature of the triglyceride. The tail group region is penetrated to a greater extent by the short chain oils than long chain alkanes, and hence swell this region to a greater extent, resulting in increased negative curvature (and reduced effective HLB).

Following are the different oils are mainly used for the formulation of microemulsion

· Saturated fatty acid-lauric acid, myristic acid, capric acid.

· Unsaturated fatty acid-oleic acid, linoleic acid, linolenic acid.

· Fatty acid ester-ethyl or methyl esters of lauric, myristic and oleic acid.

Saturated and unsaturated fatty acids have penetration enhancing property of their own and they have been studied since a long time.

Fatty acid esters have also been employed as the oil phase. Lipophilic drugs are preferably solubilize in O/W microemulsions.

Oil is selected according to the solubility of drug. This will minimize the volume of the formulation to deliver the therapeutic dose of the drug in an encapsulated form.

Aqueous phase:

It contains hydrophilic active ingredients and preservatives. Literatures reveals that buffer solutions are also used as aqueous phase. pH of the aqueous phase should be maintained between.

Surfactants:

The interfacial tension can be lowered by the use of surfactant to a very small value which will facilitates dispersion process during the preparation of the microemulsion and provide a flexible film that can readily deform around the droplets and be of the appropriate lipophilic character to provide the correct curvature at the interfacial region.

Surfactants used to stabilize microemulsion system may be

· Non-ionic

· Zwitterionic

· Cationic

· Anionic surfactants.

Non-ionic surfactants are generally considered to be acceptable for oral ingestion. Few surfactants for oral administration are polyoxyl 35 castor oil (Cremophor EL), polyoxyl 40 hydrogenated castor oil (Cremophor RH 40), polysorbate 20 (Tween 20), polysorbate 80 (Tween 80), d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), Solutol HS-15, sorbitan monooleate (Span 80), polyoxyl 40 stearate, and various polyglycolyzed glycerides including Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gelucire 44/14, etc.

· HLB (3-6) - W/O microemulsion

· High HLB (8-18) - O/W microemulsion

· HLB >20 requires co-surfactants to reduce their effective HLB

Co-surfactants:

The sufficient flexibility of the interfacial film to take up different curvatures required to form microemulsion over a wide range of composition is provided by the co-surfactant. Short to medium chain length alcohols are commonly added as co surfactants which further reduce the interfacial tension and increase the fluidity of the interface.

· Short chain alcohols - ethanol to butanol

· Medium chain alcohols - glycols such as propylene glycol.

The role of a co-surfactant is as following:

· Increase the fluidity of the interface.

· Adjust HLB value and spontaneous curvature of the interface by changing surfactant partitioning characteristic.

Co-solvents:

High concentrations of surfactants about 30% w/w are required for the production of stable microemulsion. For oral delivery, organic solvents such as, ethanol, propylene glycol (PG), and polyethylene glycol (PEG) are suitable, and they enable the dissolution of large quantities of either the hydrophilic surfactant or the drug in the lipid base. These solvents can even act as co-surfactants in microemulsion systems.

Structure of Microemulsion:

The interface is continuously and spontaneously fluctuating in dynamic system like Microemulsions or Micellar emulsion⁽³⁴⁾. Structurally, they are divided into oil in water (O/W), water in oil (W/O) and bi-continuous microemulsions.

· W/O microemulsions - water droplets are dispersed in the continuous oil phase

· O/W microemulsions - oil droplets are dispersed in the continuous aqueous phase

· Bi-continuous microemulsions - amount of water and oil are similar

The mixture oil water and surfactants are able to form a wide variety of structure and phase depending upon the proportions of component.

Types of microemulsion systems:

According to Winsor, there are four types of microemulsion phases exists in equilibria, these phases are referred as Winsor phases. They are,

Winsor I: With two phases, the lower (O/W) microemulsion phases in equilibrium with the upper excess oil.

Winsor II: With two phases, the upper microemulsion phase (W/O) microemulsion phases in equilibrium with lower excess water.

Winsor III: With three phases, middle microemulsion phase (O/W plus W/O, called bi-continuous) in equilibrium with upper excess oil and lower excess water.

Winsor IV: In single phase, with oil, water and surfactant homogenously mixed.

Difference Between Emulsion And Microemulsion:

Emulsions and Microemulsions (Fig.2) are both stable dispersions of oil-in-water or water-in-oil. Surfactants are the principal agents that enable oil and water to mix. Emulsions are stable dispersions of immiscible liquids, but they are not thermodynamically stable. The following properties shows the different between emulsion and Microemulsions. (Table 1).

Fig :Emulsion and Microemulsions preparation.

Table 1: Difference between emulsion and Microemulsions

Property	Emulsion (Macroemulsion)	Microemulsion
Appearance	Cloudy	Transparent
Optical isotropy	Anisotropic	Isotropic
Interfacial tension	High	Ultra low
Microstructure	Static	Dyanamic
Droplet size	>500nm	20-200nm
Stability	Thermodynamically unstable	Thermodynamically stable and long shelf life
Phases	Biphasic	Monophasic
Preparation	Require a large input of energy	Facile preparation
Cost	Higher cost	Lower cost
Viscosity	High viscosity	Low viscosity with Newtonian behavior
Turbidity	Turbid	Transparent
Cosurfactant used	No	Yes
Surfactant concentration	1-20 %	>10%
Size range	0.5 – 5 μ	<0.1 μ
Molecular packing	Inefficient	Efficient
Micelle diamete	20 nm +	3- 20 nm
Contact position	Direct oil / water contact at the interface	No direct oil in water contact at the interface

METHOD OF PREPARATION:^(35-36)

Phase Titration Method

With the help of phase diagrams microemulsions can be depicted and are prepared by the spontaneous emulsification method (phase titration method). They are formed along with various association structures (including emulsion, micelles, lamellar, hexagonal, cubic, and various gels and oily dispersion) depending on the chemical composition and concentration of each component. The essential aspect of the study is to understand their phase equilibrium and demarcation of the phase boundaries. The quaternary phase diagram (four component system) is time consuming and difficult to interpret and hence pseudo ternary phase diagram is often constructed to find the different zones including microemulsion zone. The region can be separated into W/O or O/W microemulsion by simply considering the composition that is whether it is oil rich or water rich. Observations should be made carefully so that the metastable systems are not included.

Phase Inversion Method:

Phase inversion of microemulsion occurs as a result of addition of excess of the dispersed phase or in response to temperature. For non-ionic surfactants, this can be achieved by changing the temperature of the system, forcing a transition from an O/W microemulsion at low temperatures to a W/O microemulsion at higher temperatures (transitional phase inversion). During cooling, the system crosses a point of zero spontaneous curvature and minimal surface tension, promoting the formation of finely dispersed oil droplets. This method is referred to as phase inversion temperature method. Instead of the temperature, other parameters such as salt concentration or pH value may be considered as well instead of the temperature alone.

Characterization of Microemulsion:

In contrast to their ease of production, microemulsions are very difficult to characterize principally because of their wide variety of structures. For this reason, the use of several techniques is often required in order to characterize microemulsion systems. An understanding of the properties of the vehicle is an important requirement for optimizing drug delivery. Additionally, factors affecting drug release, stability, and structure need to be understood in order to establish the potential, and also limitations of microemulsion formulations. A variety of techniques, such as NMR spectroscopy, electrical conductivity, self-diffusion, small-angle neutron scattering, quasi-elastic light scattering, and fluorescence spectroscopy, have been employed to characterize these systems.

Microscopy:

Although polarizing microscopy confirms the optical isotropy of the microemulsion system, conventional optical microscopy cannot be used for studying microemulsion systems because of the small droplet size diameter which is typically less than 150 nm. However, transmission electron microscopy (TEM) combined with freeze fracture techniques have been successfully applied for the study and characterization of microemulsions^(37,38). The sensitivity of microemulsion structure to temperature and the potential introduction of experimental artifacts during manipulation are of some concern with this approach. Other problems are: (1) high microemulsion vapour pressure, which is not compatible with low pressures used in microscopy, (2) electrons may induce chemical reactions, thus, altering microemulsion structure, and (3) lack of contrast between the microemulsion structure and its environment. The introduction of controlled environmental chambers as well as improvements in thermal fixation now permit very fast sample cooling rates to be achieved without crystal formation. The techniques of Cryo-TEM and freeze fracture-TEM, which have evolved from these advances, permit direct visualization of the microemulsion structure with fewer problems of artifactual results⁽³⁹⁾.

NMR:

Self-diffusion is the random movement of a molecule in the absence of any concentration gradient, and this movement reflects the environment where the molecule is localized. If a molecule is confined in a close aggregate, such as micelles, its self-diffusion will be two or three orders of magnitude lower than the expected self-diffusion coefficient from a pure solvent. Therefore, in w/o microemulsions, the self-diffusion of water molecules is slow, whereas,the diffusion of the oil molecules is high. Conversely, for O/W microemulsions the reverse is found. In bicontinuous structures, both oil and water molecules exhibit high self-diffusion coefficients. Microemulsion structure has been characterized as using self-diffusion measurements of the components, obtained by proton Fourier transform pulse-gradient spin-echo NMR (PGSE NMR)⁽⁴⁰⁾.

Conductivity and viscosity:

The nature of the microemulsion and detection of phase inversion phenomena can be determined using classical rheological methods and by conductivity determination. Viscosity determination also provide useful information on how the colloidal systems may influence drug release. The likely systems present are, for example, vesicles with multilamellar layers, rod-like or worm-like reverse micelles. Water-continuous microemulsions display high conductivity values, whereas oil-continuous systems should have poor or no conductivity⁽⁴¹⁾. Previously, it has been demonstrated that microemulsions may also exhibit percolation phenomena at certain volume fractions of water (Фp) termed the percolation threshold⁽⁴²⁾. When the water fraction is below Фp, the system behaves as an insulator, whereas the effective conductivity increases sharply at values of the water fraction slightly higher than Фp ⁽⁴³⁾. According to the percolation concept, these electrical properties result from the attractive interactions between water globules, characteristic of bicontinuous structures⁽⁴⁴⁾.

Fluorescence spectroscopy:

Fluorescence spectroscopy measures the ease of movement of the fluorescent probe molecules in the microemulsions. This is controlled by diffusion, which inversely with the viscosity of the medium and with the microemulsion type. In water-continuous microemulsions, the propagation of the excitation is inhibited because of the slow diffusion of the water-insoluble fluorescent (e.g. pyrene) molecules. On the other hand, oil continuous microemulsions should produce a similar excimer formation to that of the pure oil⁽⁴⁵⁾.

Interfacial tension:

The formation and the properties of microemulsion can be studied by measuring the interfacial tension. Ultralow values of interfacial tension are correlated with phase behavior, particularly,the existence of surfactant phase or middle-phase microemulsions in equilibrium with aqueous and oil phases. Spinning-drop apparatus can be used to measure the ultralow interfacial tension. \ Interfacial tensions are derived from the measurement of the shape of a drop of the low-density phase, rotating it in cylindrical capillary filled with high-density phase. To determine the nature of the continuous phase and to detect phase inversion phenomena, the electrical conductivity measurements are highly useful. A sharp increase in conductivity in certain W/O microemulsion system was observed at low volume fractions and such behavior was interpreted as an indication of a “percolative behavior” or exchange of ions between droplets before the formulation of bi continuous structures. Dielectric measurements are a powerful means of probing both structure and dynamic feature of microemulsion systems⁽⁴⁶⁾.

Scattering techniques for microemulsion characterization:

Small-angle X-ray scattering techniques have been used to obtain information on droplet size and shape. Using synchrotron radiation sources, in which sample-to-detector distances are bigger, significant improvements have been achieved. With synchrotron radiation more defined spectra are obtained and a wide range of systems can be studied, including those in which the surfactant molecules are poor X-ray scatters. Small-angle neutron scattering, however, allows selective enhancement of the scattering power of different microemulsion pseudophases by using protonated or deuterated molecules.

Static light scattering technique has also been widely used to determine microemulsion droplet size and shape. In this technique, the intensity of scattered light is generally measured at various angles and for different concentration of microemulsion droplets.

Dynamic light scattering, which is also referred as photon correlation spectroscopy (PCS), is used to analyze the fluctuations in the intensity of scattering by droplets due to Brownian motion. The self-correlation is measured that gives information on dynamics of the system. This technique allows the determination of z-average diffusion coefficients D. In the absence of inter-particle interactions, the hydrodynamic radius of the particles, can be determined from the diffusion coefficient using the Stokes-Einstein equation as follows:

D = kT/6πηRH,

Where, k is Boltzmann constant, T is the absolute temperature and η is the viscosity of the medium, RH is the relative humidity⁽⁴⁷⁾.

Applications of Microemulsions:

u Pharmaceutical Applications:

· Parenteral delivery

· Oral drug delivery

· Topical drug delivery

· Ocular drug delivery

· Pulmonary drug delivery

· Microemulsions in biotechnology

u Other Applications:

· Microemulsion in enhanced oil recovery

· Microemulsions as fuels

· Microemulsions as lubricants, cutting oils and corrosion inhibitors

· Microemulsions as coatings and textile finishing

· Microemulsions in detergency

· Microemulsions in cosmetics

· Microemulsions in agrochemicals

· Microemulsions in food

· Microemulsions in environmental remediation and detoxification

· Microporous media synthesis (microemulsion gel technique)

· Microemulsions in analytical applications

· Microemulsions as liquid membranes

· Novel crystalline colloidal arrays as chemical sensor materials^(48,49).

Figure 1. The structure of micelles. M= Micelles for o/w microemulsion, RM= Reverse micelles for w/o microemulsion

Evaluation of Microemulsions:

The microemulsions are evaluated by the following techniques, they are

(A) Measurement of pH:

The pH values of Microemulsions were determined using digital pH meter standardized using pH 4 and 7 buffers before use.

(B) Globule Size Analysis of the Microemulsions:

The average globule size of the microemulsions were determined by the photon correlation spectroscopy.

Measurements were carried at an angle of 90°at 25°C. Microemulsions were diluted with double distilled water

to ensure that the light scattering intensity was within the instrument’s sensitivity range. Double distilled water was filtered through 0.45μ membrane filters prior to globule size determination.

(C) Measurement of electrical conductivity:⁽⁵⁰⁾

The electrical conductivity of microemulsions was measured with a conductivity meter equipped with inbuilt magnetic stirrer. This was done by using conductivity cell consisting of two platinum plates separated by desired distance and having liquid between the platinum plate acting as a conductor.

(D) Rheological studies:

Changing the rheological characteristics help in determining the microemulsions region and its separation from other related structure like liquid crystals bicontinuous microemulsions are dynamic structure with continuous fluctuation occurring between the bicontinuous structure, swollen reverse micelle, and swollen micelle.

(E) Viscosity Measurements:⁽⁵¹⁾

Microemulsions are generally low viscosity systems. The viscosity measurements were performed using Brookfield viscometer at single mode (Spindle C-50). All the measurements were done in triplicate for 60 seconds at a temperature of 23.50C.

(F) Polydispersity:

This property is characterized by Abbe refractometer.

(G) Phase behavior studies:

Visual observation, phase contrast microscopy and freeze fracture transmission, electron microscopy can be used differentiate microemulsions from liquid crystals and coarse emulsions. Clear isotropic one phase system are identified as microemulsions where as opaque system showing bifringence when viewed by crosploarized light microscopy may be taken as liquid crystalline system .

(H) Freeze thawing method:⁽⁵²⁾

Freeze thawing was employed to evaluate the stability of formulations. The formulations were subjected to 3 to 4 freeze-thaw cycles, which included freezing at – 4°C for 24 hours followed by thawing at 40°C for 24 hours. Centrifugation was performed at 3000 rpm for 5 minutes. The formulations were then observed for phase separation. Only formulations that were stable to phase separation were selected for further studies.

(I) Scattering techniques:

Scattering technique such as Small angle neutron scattering (SANS), Small angle x-ray scattering (SAXS), Dynamic light scattering (DLS) are used for studying Microemulsions structure especially on the size, shape and dynamics of the components.

(J) Nuclear Magnetic Resonance Studies:⁽⁵³⁾

The Fourier transform pulsed-gradient spin-echo (FTPGSE) technique uses the magnetic gradient on the samples and it allows simultaneous and rapid determination of the self-diffusion coefficients of many components.

(K) Study of microstructure of Microemulsions:⁽⁵⁴⁾

Transmission Electron Microscopy (TEM) is the most important technique for the study of microstructures of microemulsions because it directly produces images at high resolution and it can capture any co-existent structure and micro-structural transitions. There are two variations of the TEM technique for fluid samples.

1. The cryo-TEM analyses in which samples are directly visualized after fast freeze and freeze

fructose in the cold microscope.

2. The Freeze Fracture TEM technique in which a replica of the specimen is images under RT

conditions.

(L) Identification test for type of microemulsions:⁽⁵⁵⁾

1. Dilution test:

If the continuous phase is added in microemulsions, it will

not crack or separate into phases. If water is added in o/w

type of microemulsions it will remain stable.

2. Staining test:

Water soluble dye such as methylene blue or amaranth was added in water and microemulsion was prepared with oil and surfactant. A drop of Microemulsions was observed under microscope. Background was found to be blue / red and globule will appear colorless respectively.

(M) Clarity test:

It observed visually, because microemulsions are clear and transparent.

(N) Dilutability test:

The Microemulsions formed were diluted in 1:10, and 1:100, ratios with double distilled water to check if the system shows any signs of separation.

(0) Zeta potential measurement:⁽⁵⁶⁾

It must be negative or neutral, which indicate that droplets of micro emulsion having no charge that is system is stable. Zeta potential is determined by using Zetasizer. Zeta potential is essentially useful for assessing flocculation since electrical charges on particles influence the rate of flocculation.

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Received on 18.03.2016 Modified on 05.04.2016

Res. J. Pharm. Dosage Form. and Tech. 2016; 8(2):161-170.

DOI: 10.5958/0975-4377.2016.00021.5