Stability

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Chapter: Pharmaceutical Drugs and Dosage: Dosage forms - Emulsions

Emulsions must demonstrate physical, chemical, and microbial stability throughout their shelf life under recommended packaging and storage conditions.


Stability

Emulsions must demonstrate physical, chemical, and microbial stability throughout their shelf life under recommended packaging and storage conditions.


Physical instability

Physical stability of an emulsion is characterized by the maintenance of elegance with respect to appearance, odor, color, taste, opacity, and viscos-ity. Four major phenomena are associated with the physical instability of emulsions: (1) flocculation, (2) creaming, (3) coalescence, and (4) breaking. These phenomena are schematically illustrated in Figure 17.2. Flocculation is discussed under the chapter on suspensions.


Figure 17.2 Schematic illustrations of different types of instability of emulsions.

Creaming and sedimentation

Creaming is the upward movement of dispersed oil droplets in an o/w emulsion, whereas sedimentation, the reverse process, is the downward movement of dispersed-phase droplets. Creaming involves visually evident separation of two layers that differ primarily in the number density of the dispersed phase, and, thus, show optical differences. These processes take place due to the density differences in the two phases and can be reversed by shaking. Creaming is undesirable because a creamed emulsion increases the likelihood of coalescence due to the closer proximity of the globules in the cream and because of the nonuniformity of the creamed emulsion. The propensity and rate of creaming is influenced by factors similar to those involved in the sedimentation of suspensions and are indicated by the Stoke’s Law, as discussed in a preceding Section 17.4.3.

Aggregation, coalescence, creaming, and breaking

Aggregation involves close packaging/contact of the dispersed-phase drop-lets, but the droplets do not fuse. Aggregation is, to some extent, reversible. Coalescence is the process by which emulsified globules merge with each other to form larger globules. Coalescence is an irreversible process because the film that surrounds the individual globules is destroyed. It leads to pro-gressive increase in the size of the dispersed phase, ultimately leading to breaking of the emulsion. Breaking of an emulsion refers to complete sepa-ration of the two liquid phases. Creaming is a reversible process, whereas breaking is irreversible. When breaking occurs, simple mixing fails to resus-pend the globules in a stable emulsified form, since the film surrounding the particles has been destroyed and the oil tends to coalesce. The proportion of the volume of emulsion occupied by creamed layer is an indicative of the stability of an emulsion. Greater the proportion of the creamed layer, more stable the emulsion. Flocculation, which leads to weak interactions between dispersed-phase droplets, can stabilize an emulsion by increasing the dura-tion of time it takes for creaming and the proportion of the creamed phase.

Formation of a thick interfacial film is essential to minimize coalescence. In addition, increasing the mechanical strength of the interfacial barrier, such as by closer packing of the interfacial surfactant monolayer, reduces the propensity toward coalescence. Increasing the viscosity of the continu-ous phase helps to stabilize the dispersed phase and minimizes coalescence.

Particle size does not correlate well with increased/decreased breaking, nor does viscosity. Phase volume is an important consideration in the stability of an emulsion. For example, at greater than ~74% of oil in an o/w emulsion, the oil globules often coalesce and breaking occurs. Thus, a critical concentra-tion is defined in terms of the concentration of the internal phase above which the emulsifying agent cannot produce a stable emulsion of the desired type. Generally, a phase-volume ratio of 50:50 results in the most stable emulsion.

Phase inversion

An emulsion is said to invert when it changes from an o/w to a w/o emul-sion, or vice versa. Phase inversion can occur by the addition of an elec-trolyte or by changing the phase volume ratio. Addition of monovalent cations promotes the formation of o/w emulsions, whereas the addition of divalent cations increases the propensity toward the formation of w/o emulsions. For example, an o/w emulsion stabilized with sodium stearate can be inverted to a w/o emulsion by adding calcium chloride to form cal-cium stearate.


Chemical instability

The API must be chemically stable in the dosage form throughout the shelf life of the product under recommended packaging and storage conditions in terms of both potency and impurities. The drug product must meet pre-determined requirements of minimum potency of the API and maximum levels of known and unknown impurities. Factors governing the reaction kinetics of the API, such as the reactivity of functional groups and the kinetics of reactions are no different for emulsion dosage forms than other solution-based dosage forms. Nevertheless, separation of the reacting spe-cies in the oily and aqueous phases can minimize reactivity and improve stability of a drug in an emulsion.


Microbial growth

Microbial load of a dosage form must be controlled within the compendial and the regulatory levels. In addition to the health risks of microbial growth, microorganisms in an emulsion can cause physical separation of the phases. Preservatives must be added in adequate concentrations in the formulations to resist microbial growth. The preservative should be concentrated in the aqueous phase because bacterial growth will normally occur there. The oil and water partition coefficient of the preservatives should be considered to calculate the concentration of the surfactant in the aqueous phase, which needs to be above the antimicrobial concentration. The para-bens (methylparaben, propylparaben, and butylparaben) are the commonly used preservatives in emulsions.

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