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.
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.
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.
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.
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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