Selection of additives  Manufacturing  Stability considerations  Evaluation  Drug excipient interaction and incompatibilities

The microemulsion concept was introduced as early as 1940s by Hoar and Schulman who generated a clear single-phase solution by titrating a milky emulsion with hexanol. Microemulsions are clear, transparent, thermodynamically stable, heterogeneous, biphasic liquid dosage forms which are dispersions of oil and water, stabilized by an interfacial film of surfactant frequently in combination with a co-surfactant.

A microscopic, single-phase, thermodynamically stable system of oil and water stabilized by surfactant molecules.

transparent emulsion, micellar solution, solubilized system, swollen micelles Macroemulsion: 0.1-100 microns Coarse emulsion: 10-100 microns Submicron emulsion : < 1microns Microemulsions: 10-100 nm (
o/w

0.01 dynes/cm)

Major Goals To deliver hydrophilic as well as lipophilic drugs acting as drug carriers because of its Improved drug solubilization , Long shelf life, Ease of preparation & Improved bioavailability Advantages

These are thermodynamically stable and require minimum energy for formation. Ease of manufacturing and scale-up Improved drug solubilization and bioavailability. Wide applications in colloidal drug delivery systems for the purpose of drug targeting and controlled release. The formation of microemulsion is reversible. They may become unstable at low or high temperature but when the temperature returns to the stability range, the microemulsion reforms. Improve the efficacy of a drug, allowing the total dose to be reduced and thus minimizing side effects. Drawbacks Use of large concentration of surfactant and co-surfactant is necessary for stabilizing the nanodroplets.

Limited solubilizing capacity for high-melting substances The surfactant must be nontoxic for using pharmaceutical applications Microemulsion stability is influenced by environmental parameters such as temperature and pH. DIFFERENCE BETWEEN MICRO AND MACROEMULSION Microemulsion contain particles at least an order of magnitude (<0.1 m) smaller than those in macroemulsions (2 - 20 m). Microemulsions are clear while macroemulsions are cloudy. Microemulsions form spontaneously while macroemulsions ordinarily require a large input of energy. Due to smaller droplet size of Microemulsions, droplets contact is large with the surface area of adsorbing tissue, thus absorption is more than macroemulsion. Microemulsions are stable with respect to separation into their components while macroemulsions may have a degree of kinetic stability but ultimately separates. Oil in water microemulsions wherein oil droplets are dispersed in the continuous aqueous phase Water in oil microemulsions wherein water droplets are dispersed in the continuous oil phase;

Bi-continuous microemulsions wherein micro domains of oil and water are inter dispersed within the system. In all three types of microemulsions, the interface is stabilized by an appropriate combination of surfactants and/or co-surfactants. SELECTION OF COMPONENTS Mainly four components are necessary for the preparation of microemulsion i.e., 1) Surfactant, 2) Co-surfactant, 3) Oil and 4) Aqueous phase. 1) SELECTION OF SURFACTANT Surfactants or emulsifiers are the components that contain two separate regions, hydrophilic region (water liking) & hydrophobic region (water hating) which render the material soluble in hydrocarbon solvent. The surfactant (s) chosen should Have lower interfacial tension. Provide flexible film that can readily form round small droplets. Appropriate hydrophilic lipophilic characters. Number of Surfactant selection systems are available but mostly four will be considered, a. Hydrophilic Lipophilic Balance (HLB). b. Phase Inversion Temperature (PIT). c. Cohesion Energy Ratio (CER) d. Co-surfactant Partitioning 2) SELECTION OF CO-SURFACTANT The co-surfactant act as a partition between the oil phase and interphase. Normally surfactant is in the interphase in microemulsion system, a smaller fraction of cosurfactant finds in interphase with the balance remaining in the oil phase. It changes the composition of oil and so there is a change in original oil/water tension. Mostly alcohols are used as co-surfactant in microemulsions. 3) SELECTION OF OILS In general highly polar oils are often prescribed. The molecular volume and chemical nature of oils has been also been regarded as one of the important factor in the preparation of microemulsions. Quantity of oil, which is to be dispersed in the surfactant and co-surfactant, should be checked.

Combination of oil and surfactant reduced interfacial tension or decrease partitioning coefficient (Ko/w)a PREPARATION OF MICROEMULSION Construction of Phase Diagram: A pseudoternary phase diagram is constructed to determine the composition of an Aq. Phase , an oil phase & a surfactant : co-surfactant Phase that will yield a Microemulsion (M.E.). It is constructed to define the extent & nature of M.E. region. The different phases are mixed in different proportion to construct the phase diagram & define M.E. region Since 4 chemical species were incorporated in M.E.; one of the components (Cosurfactant) is in fixed ratio with surfactant. Each of the 3 components for a system is titrated until a phase change between M.E. & twophase mixture was observed. PREPARATION OF MICROEMULSION Can be prepared simply by blending oil, water, surfactant and co-surfactant with mild agitation. The orders of mixing the components are generally considered not to be critical, since microemulsions form spontaneously. Although microemulsification is a spontaneous process, the driving forces are small and the time taken for these systems to reach the equilibrium interfacial tension can be long. ENTRAPMENT OF DRUG The drug molecules are primarily solubilized in the entrapped phase, i.e. the oil phase for o/w microemulsion and the water phase for w/o microemulsion. Entrapment efficacy depends on the solubility of the drugs into the oils employed. PREPARATION OF MICROEMULSION Microemulsion is formed when the interfacial tension at the O/W interphase are brought very low level. The interfacial tension is kept highly flexible and fluid. THERMODYNAMIC STABILITY The thermodynamic stability is due to the free energy formation of microemulsion to be contributions of three components. 1. Interfacial energy 2. Energy Interaction between droplets. 3. Entropy of dispersion. The free energy of microemulsion formation can be considered to depend on the extent to which surfactant lowers the surface tension of oil water interface and change in entropy of the system such that. Where, = Free energy formation = Change in interfacial area on microemulsion.

= Surface tension between oil water interface. T = Temperature = Change in entropy of the system When the interfacial tension is made sufficiently low that the interfacial energy becomes comparable to or even lower than the entropy of dispersion. The free energy of formation of the system becomes zero or negative. This explains the thermodynamic stability of micro emulsions. The co-surfactant along with surfactant lower the interfacial tension to a very small even transient negative value. At this value, interface would expand to form fine dispersed droplets. Adsorb more surfactant and co-surfactant until their bulk condition is depleted enough to make interfacial tension positive again. This process is known as Spontaneous Emulsification which forms the micro emulsion. EVALUATION OF MICROEMULSION There are no such methods to evaluate microemulsion but some physicochemical parameters were checked. Measurement of droplet size. Conductivity. Viscosity. Surface Tension. Refractive Index. MEASUREMENT OF DROPLET SIZE Transmission electron microscopy Dynamic light scattering Small-angle neutron scattering Small-angle x-ray scattering Malvern Master size CONDUCTIVITY It measures the current carrying capacity of given number of ions in solution. It is measured by using Conductometer. The instrument was calibrated by using KCl solution at room temperature. The conductance of samples was measured at room temperature VISCOSITY Viscosity is used to measure internal friction of fluid. Viscosity studies of optimized formula were performed by viscometry method. It is measured with Ostwald viscometer. L1 / L2 = V 1 t1 / V2 t2 SURFACE TENSION It is measured by using Stalagnometer. In this case surface tension of oil phase, aqueous phase and optimized microemulsions formulation were calculated. Calibration of Stalagnometer was carried out by using water. The sample filled in the Stallagnometer up to the mark. Number of drops was counted as liquid travels between two marks. The following formula used for calculation, K1 / K2 = n2d1 / n1d2. REFRACTIVE INDEX

It is used to determine the concentration of one substance dissolved in another substance. Light passes through less dense to the more dense substance. The relative value of this effect between two substances is given by refractive index. Abbe s refractometer was used for the determination of refractive index of oil, water and microemulsion.