Formulation considerations

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Chapter: Pharmaceutical Drugs and Dosage: Dosage forms - Emulsions

Emulsions are inherently thermodynamically unstable due to the differ-ences in the molecular forces of interaction between the molecules of the two liquid phases.

Formulation considerations

Emulsions are inherently thermodynamically unstable due to the differ-ences in the molecular forces of interaction between the molecules of the two liquid phases. The oxygen and hydrogen atoms in the water molecules in the aqueous phase bond with surrounding water molecules through dipolar and hydrogen-bonding interactions, whereas the carbon atoms in the oil phase bond with the surrounding molecules predominantly through weak hydrophobic and Van der Waals interactions. Creation of surface of interaction between the two phases is thermodynamically unfavorable. Therefore, production of emulsions requires the introduction of energy into the system. This is accomplished by trituration on the small scale and homogenization on the pilot and large scale. In addition, interfacial mol-ecules of both phases must be stabilized against the tendency for the self-interaction of phases, which can lead to the coalescence and collapse of the dispersed phase.

Minimization of interfacial free energy

Dispersion of insoluble phases results in thermodynamic instability and high total free energy of the system. Since every system tends to sponta-neously reduce its energy to a minimum, all emulsions tend to separate into the two insoluble phases with time. When one liquid is broken into small globules, the interfacial area of the globules is much greater than the minimum surface area of that liquid in a phase-separated system. Thus, the dispersed phases tend to coalesce or phase separate to minimize the surface of interaction between the two phases. This phase separation is driven by greater forces of interaction between molecules of the same phase than between the molecules of different phases. A phase-separated system represents the state of minimum surface-free energy.

The surface-free energy of an emulsion is evident as the interfacial tension between the two phases. Addition of a surfactant to an emulsion leads to preferential translocation of the surfactant molecules to the interface of the two liquid phases since a surfactant is amphiphilic and molecules in both phases form attractive interactions with the surfactant molecule. The pres-ence of a surfactant at the interface of dispersed-phase globules lowers the interfacial tension. Reduction of the interfacial tension delays the kinetics of coalescence of the two phases. Frequently, combinations of two or more emulsifying agents are used to adequately reduce the interfacial tension by forming a rigid interfacial film.

Optimum-phase ratio

The ratio of volume of the disperse phase to the volume of the dispersion medium (phase ratio) greatly influences the characteristics of an emul-sion. The optimum-phase volume ratio is generally obtained when the internal or dispersed phase is about 40%–60% of the total quantity of the product. A conventional emulsion containing less than 25% of the dispersed phase has a high propensity toward creaming or sedimentation. Nevertheless, a combination of proper emulsifiers and suitable process-ing technology makes it possible to prepare emulsions with only 10% disperse phase without stability problems. Such a combination of emul-sifiers includes the use of a hydrophilic emulsifier in the aqueous phase and a hydrophobic emulsifier in the oil phase. Such a combination leads to the formation of a closely packed surfactant film at the interface. For example, a combination of sodium cetyl sulfate and cholesterol leads to a closely packed film at the interface that improves emulsion stability. On the other hand, sodium cetyl sulfate and oleyl alcohol do not form a closely packed or condensed film. Consequently, this combination results in a poor emulsion.

Size, viscosity, and density: Stoke’s law

Creaming or sedimentation of the dispersed phase in an emulsion is math-ematically modeled by Stoke’s law (see Chapter 16), which indicates that the physical stability of an emulsion can be enhanced by

1.        Decreasing the globule size of the internal phase. The dispersed glob-ule size less than 5 μm in diameter contributes to good physical stabil-ity and dispersion of the emulsion.

2.        Increasing the viscosity of the system. Gums and hydrophilic poly-mers are frequently added to the external phase of an o/w emulsion to increase viscosity, in addition to reducing the interfacial tension and forming a thin film at the interface. Higher the viscosity of the continuous phase, lower the Brownian motion, collision frequency, and energy of collisions of the dispersed-phase globules. Increasing the viscosity can have an unwanted effect of reduction of deliverable volume from the container because highly viscous liquids tend to adhere to the container. In addition, the non-Newtonian viscosity behavior of the emulsion is an important consideration. For example, shear-thinning system may be preferred, whereas a shear-thickening system would be undesirable.

3.        Reducing the density difference between the dispersed phase and the dispersion medium. This reduces the creaming tendency by minimiz-ing the driver for separation and preferential accumulation of the dis-persed phase in a particular direction.

Zeta potential

Emulsions can be stabilized by electrostatic repulsion between the droplets. High zeta potential (see Chapter 16) on the surface of the droplets causes the dispersed-phase droplets to repel each other and thereby resist colli-sions due to Brownian motion, mixing, and gravitational forces. Thus, the droplets remain suspended for a prolonged period of time. For example, if negatively charged lecithin is adsorbed at the droplet surface it creates a net negative charge and zeta potential on the dispersed-phase droplets. Highly charged dispersed-phase droplets, however, can coalesce irrevers-ibly when colliding with high enough energy to overcome the repulsive forces. Optimizing the zeta potential of the dispersed phase to facilitate flocculation can minimize a system’s propensity toward undesirable coales-cence. The zeta potential can be optimized by the addition of positively charged electrolytes to the outer, continuous phase. At appropriate zeta potential, the system achieves a state where flocculation is facilitated over coalescence.

Table 17.1 lists the composition of two typical o/w pharmaceutical emulsions.

Table 17.1 Examples of emulsion formulations

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