Formulation of Multiple Emulsions

Multiple emulsions are complex systems of emulsions of emulsions. Both water-in-oil-in-water (W/O/W) and oil-in-water-in-oil (O/W/O) multiple emulsions have potential appHcations in various fields. The W/O/W multiple emulsion may be considered as a water/water emulsion whereby the internal water droplets are separated by an oily layer (membrane). The internal droplets might also consist of a polar solvent such as glycol or glycerol, which may contain a dissolved or dispersed active ingredient (a.i.). The O/W/O multiple emulsion can be considered as an oil/oil emulsion separated by an aqueous layer (membrane). 

Formulation of D erse Systems Science and Technology, First Edition. Tharwat F. Tadros. 

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Knowledge of surfactant equilibration and interactions will probably lead to improved formulations of multiple emulsions. Failing this the use of polymerisable surfactants can lead to obvious strengthening of interfacial barriers and allow control of stability and drug release. Nonetheless further detailed work on both w/o/w and o/w/o systems is justified. 

In this chapter, the formulation of multiple emulsions with particular reference... 

Solid oil (paraffin wax) is superior to liquid oil in formulations of multiple emulsions as a stable rigid oil membrane is formed that hinders the migration of additives from the inner water phase. ... 

The number of the constituent phases of a disperse system can be higher than two. Many commercial multiphase pharmaceutical products cannot be categorized easily and should be classified as complex disperse systems. Examples include various types of multiple emulsions and suspensions in which solid particles are dispersed within an emulsion base. These complexities influence the physicochemical properties of the system, which, in turn, determine the overall characteristics of the dosage forms with which the formulators are concerned. 

In addition to the necessary protection of the contents of the emulsion droplets, effective encapsulation technology requires that the release of the active matter be controlled at a specified rate. Benichou et aL (2004) have demonstrated that a mixture of whey protein isolate (WPI) and xanthan gum can be successfully used for the controlled release of vitamin Bi entrapped within the inner aqueous phase of a multiple emulsion. The release profile, as a function of the pH of the external aqueous phase, is plotted in Figure 7.25. We can observe that the external interface appears more effectively sealed against release of the entrapped vitamin at pH = 2 than at pH = 4 or 7. It was reported that an increase in the protein-to-potysaccharide ratio reduced the release rate at pH = 3.5 (Benichou et aL, 2004). More broadly, the authors suggest that compatible blends of biopolymers (hydrocolloids and proteins) should be considered excellent amphiphilic candidates to serve as release controllers and stability7 enhancers in future formulations of double emulsions. So perhaps mixed compatible biopolymers wall at last allow researchers to... 

The formulation and stability of multiple emulsion systems has recently been reviewed by the present authors (17). 

This led to the inclusion of two types of particles into the emulsions and the formation of multiple emulsions. For example, hydrophobically modified particles were dispersed in toluene, while hydrophilically modified particles were dispersed in water. Emulsification of this system produced water-in-toluene-in-water or toluene-in-water-in-toluene multiple emulsions. Formulations of one type over the other were achieved... 

Silva Chunha, A. Grossiord, J.L. Seiller, M. The formulations and industrial applications of multiple emulsions an area of fast development. In New Products and Applications in Surfactant Technology, Karsa, D.R., Ed. CRC Press LLC Boca Raton, FL, 1998 Vol. 1, 205-226. 

The emulsions so far described have been mainly of the simple 0/W type. However, because of their utility in other fields (e.g., cosmetology), an interest is developing in food applications of multiple emulsions, i.e., water-in-oil-in-water emulsions, since fliey modify the behavior of the fat and also offer the potential to carry, in their interior water droplets, materials of nutritional interest (172, 173). However, flic formulation and con trol of such preparations is much more difficult than for simple emulsions (174). The basic principles of such emulsion formulation are well known the water droplets within the oil droplet need to be stabilized using a mixture of lipophilic emulsifiers, whereas the stabilization of the oil droplets requires rather a hydrophilic surfactant. Evidently, the preparation of such emulsions cannot be preformed in a single stage, but requires the preparation of a W/O emulsion first, and then dispersion of this emulsion into an aqueous medium. 

Two kinds of multiple emulsions exist. Water-in-oil-in-water (W/OAV) emulsions are made of oil globules eon-taining water droplets and are dispersed in water. Oil-in-water-in-oil (OAV/0) emulsions are made of water globules containing oil droplets and are dispersed in oil. These emulsions have been formulated to trap speeifie substances and to effect their release at will (5,6,57-61), but... 

The other two branches of the standard inversion line are essentially vertical, and are located typically at 30% water on the negative SAD side of optimum formulation, and at 70% water on the positive side. When the water content is low, the emulsion is always W/0, regardless of the formulation. Similarly, when the oil content is low, an 0/W can be expected, whatever the formulation. In these extreme WOR regions, the phase which is present in larger volume becomes the external phase of the emulsion. It may be said that the composition dominates. However, a closer look at the conductivity value indicates the presence of multiple emulsions in the B" and zones, i.e., where the composition effects dominate over the normal formulation trend. These B" and regions have been called abnormal in opposition to the other ones which are labeled normal because they follow the Bancroft rule and the wedge theory (172). 

SM Safwai. MA Kas.se m. MA Aiita. M El-Mahdy. The formulation-perform a nee relationship of multiple emuLsions and ocular activity, J Controlled Rel 32-259-268 (1994). 

The transport mechanism of electrolytes through the oily liquid phase has been the subject of many investigations over the past decades. Nevertheless, there remains a lack of a clear understanding as to what and how various formulation parameters of multiple emulsions affect the kinetics and extent of the migration of electrolytes across the middle phase, and thereby influence the osmotic pressure. Partition coefficient, ionization, charge density, molecular weight, and molecular mobility of electrolytes can have some impact on electrolytes ability to cross the oil phase. The association of electrolytes with the surfactant, which may form inverted micelles in the oil phase, has also been considered (Chilamkurti and Rhodes, 1980). 

Numerous applications of multiple emulsions in various fields have been reported. More applications need to be realized if multiple emulsions stability is to be fully understood and approaches to stabilize multiple emulsions fully rationalized. The stability of multiple emulsions is influenced by numerous formulation and process variables. As demonstrated in this chapter, long-term multiple emulsion stability is dependent on the osmotic and Laplace pressures of the inner droplets as well as on the pressure balance between them described by the Walstra equation. Stability also equally, in some cases even more, depends on the strength of the interfacial film formed on the interface of droplets of multiple emulsions. This property can be characterized by interfacial rheology. 

Florence AT, Whitehill D. 1982. The formulation and stability of multiple emulsions. Int J Pharm 11 277-308. 

The use of an amphiphilic copolymer as a surfactant allows for an increase of the lifetime of multiple emulsions. The structural properties emulsions should thus be precisely studied. We performed direct confocal naicroscopy observations as well as light-scattering experiments in order to investigate the dynamics of the inverse droplets inside oil globules. Depending on the emulsion formulation, we showed that droplets are either unifomaly distributed inside direct globules, or they are depleted toward the inner surface of the globules. These structural differences appear to play a key role in the destabilization and release processes. 

Mechanical Stabilization by Microcrystalline Cellulose Some attempts have been made to improve the shelf-life of multiple emulsions by incorporating small solid particles in the surfactant formulations. The idea was to allow the particles to adsorb onto the oil droplets so that they can provide a mechanical barrier against coalescence (Aveyard et al., 2003). Oza and Frank (1989) were the first to develop the concept by using colloidal microcrystaUine cellulose (MCC) instead of water-soluble surfactant in W/OAV emulsions containing oil-soluble hydrophobic surfactants (Spans). Emulsions, stable for up to 1 month, contained a network of MCC particles adsorbed at the outer oil-water interface. 

Garti N. 1998. Influence of the formulation on the characteristics and stability of multiple emulsions. In Multiple Emulsions Structure, Properties and Applications, SeiUer M, Grossiord JL, eds. Paris Editions de Sante, pp 81-116. 

The two kinds of multiple emulsions considered contained in the first formulation the EMP Hydrogel in the external phase (called TRME7) and in the second formulation thickening agent the EG 56 Hydrogel (denoted EGME). 

Cosurfactant facilitates droplet size reduction in the fME range. The multiple emulsion was diluted with equal volume of ice-cold external phase (<4°C), stirred for 15 minutes, and immediately transferred to a refrigerator. The pH of the external phase was increased to about 8.0 to 8.9 and then restored to 7.4 with addition of an acid. The multiple emulsion was formed with a relatively high percentage of the secondary surfactant further a cosurfactant had to be added to reduce the size of multiple emulsion. The formulation and process variables Uke amount of surfactants, phase volume, and time period of sonication for both emulsification steps were optimized by way of the appropriate evaluation parameters, mainly solidification, droplet size, yield, viscosity, and/or stability. 

TABLE 9.1 Physicochemical characteristics of multiple emulsion formulations... 

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