Types of Multiple Emulsions

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. 

Figure 1 Schematic presentation of the three common types of multiple-emulsion droplets.

Choice of surfactant(s) for the preparation of multiple emulsions can, in principle, be made from any of the four classes of surfactants discussed in Chapter 3, although nonionics tend to be materials of choice because they are more easily tailored to meet the needs of the system. The choice will be determined by the characteristics of the final emulsion type desired, such as the natures of the various phases, additives, and solubilities. In many applications (e.g., foods, drugs, cosmetics), the choice may be further influenced by such questions as toxicity, interaction with other addenda, and biological degradation. In a given system, several different surfactants may perform adequately in terms of stability, but produce different types of multiple emulsions (A, B, or C in Figure 11.15), so that the choice will depend on application as well as function. 

Near the PIT, formation of mnltiple emnlsions is frequently observed during mixing (e.g., one or more water drops within an oil drop, which is itself dispersed in water). This type of multiple emulsion is called water-in-oil-in-water. Of course, oil-in-water-in-oil emnlsions also occnr nnder these circumstances. One can also deliberately make mnltiple emnlsions. For instance, a water-in-oil emulsion with relatively small drops is first formed by vigorous mixing with a suitable... 

F ure 1. Schematic representatian of two types of multiple-emulsion systems. The upper droplet contains a singular aqueous droplet whereas the lower droplet contains numerous aqueous droplets. 

Three types of multiple emulsions may be distinguished [16] (Figure 12.11). This classification is based on the predominance of the multiple emulsion droplet type. Using isopropyl myristate as the oil phase, 5% Span 80 to prepare the primary W/O emulsion, and various surfactants to prepare the secondary emulsion, three main types of multiple emulsions were observed [16] Type A droplets contained on a large internal droplet, similar to that observed by Matsumoto et al. [17]. This type was produced when polyoxyethylene oxide (4) lauryl ether (Brij 30) was used as secondary emulsifier at 2%. Type B droplets contained several small internal droplets. These were prepared using 2% polyoxyethylene (16.5) nonylphenyl ether (Triton X-165). Type C drops entrapped a large number of small internal droplets. These were prepared using a 3 1 Span 80-Tween 80 mixture. 

Florence and Whitehill [14] distinguished between three types of multiple emulsions, (W/O/W) that were prepared using isopropyl myristate as the oil phase, 5% Span 80 to prepare the primary W/O emulsion and various surfactants to prepare the secondary emulsion (see Chapter 12 for details). A schematic representation of some breakdown pathways that may occur in W/O/W multiple emulsions is shown in Figure 13.26. 

Florence and Whitehill [38] distinguished between three types of multiple emulsions (W/O/W) that were prepared using isopropyl myristate as the oil phase, 5 % Span 80 to prepare the primary W/0 emulsion and various surfactants to prepare the secondary emulsion (a) Brij 30 (polyoxyethylene 4 Lauryl ether) 2%. (b) Triton X-165 (polyoxyethylene 16.5 nonyl phenyl ether (2%). (c) 3 1 Span 80 Tween 80 mixtures. A schematic picture of the three structures is shown in Fig. 1.34. The most common structure is that represented by (b) whereby the large size multiple emulsion droplets (10-100 pm) contain water droplets 1 pm. A schematic representation of some breakdown pathways that may occur in W/O/W multiple emulsions is shown in Fig. 1.35. 

W/W A number of researchers have prepared a new type of multiple emulsion termed OfWfW, based on the thermodynamic incompatibility of mixed biopolymer solutions. For example, oil-in-water-in-water (O/W/W) emulsions can be prepared by mixing an OAV emulsion with a W/W emulsion. 

Figure 7.1 Schematic presentation of the two types of multiple emulsion droplets, (a) Typical O/W/O multiple emulsion droplet, (b) typical W/O/W multiple emulsion...

Many compounds with adjuvant activity are presently known (shown in Table 12.2) but only a few are applied routinely in human and veterinary vaccines. The application of the novel adjuvants are limited for several reasons, such as disappointing efficacy in the target animal species, insufficient safety, problems with large-scale preparations, and limited stability of the final formulations. Many studies have reported on O/W and W/O emulsions used as adjuvants and delivery systems for immunization (Hilgers et al., 1994a, b, 1999). The adjuvanticity of the W/O/W makes this type of multiple emulsion a suitable delivery system for immunization with prolonged release, and its interesting preparation is presented below. 

Last, the results of a very recent investigation concerning a novel type of multiple emulsion, dubbed emulsified microemulsion (EME), are herewith... 

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... 

FIGURE 13.10 Three types of produced emulsions (a) W/O emulsion, (b) 0/W emulsion, and (c) multiple emulsion. Source Li (2007). 

It should be noted that type A multiple emulsions are not encountered much in practice, while type C is difficult to prepare as a large number of small water internal droplets (which are produced in the primary emulsification process) results in a large increase in viscosity. Thus, the most common multiple emulsions used in practice are those represented by type B. 

Simple anulsions consist of dispersion of droplets of one liquid phase in another inunisable liqnid phase. Based on the type of the internal phase, two types of simple emulsions exist, namely, wato-in-oil (w/o) and oil-in-water (o/w) emulsions (Figures 58.6a and b). In w/o emulsions, the water disperses in the oil continuum phase, whereas, oil phase remains as dispersed in the water continuum phase in o/w emulsions. Emulsifiers are added to fecilitate the reduction in the surface tension amongst the immiscible phases. The type of the emulsions formed is determined by the type of the anulsifier used. Based on the size of the internal phase, simple emulsions can be divided in microemulsions and macroemulsions. If the emulsions contain more than two phases, then they are regarded as multiple emulsions. 

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. 

Several types of double emulsions have been documented. Some consist of a single, internal compartment while others have many internal droplets and are known as multiple-compartment emulsions. A schematic presentation of some double emulsions is shown in Fig. 1. The most common double emulsions are of W/O/W, but in some specific applications O/W/0 emulsions can also be prepared. The term multiple emulsion was coined historically because microscopically it appeared that a number (multiple) of phases were dispersed one into the others. In most eases it was proven that in practice most systems are composed of double (or duplex) emulsions. A more suitable and more accurate term for such systems should be, therefore, emulsified emulsions. ... 

Emulsions with complex multilayered stmctures are referred to as multiple emulsions. A well-known example is a double emulsion, in which microdroplets that enclose even smaller droplets are suspended in a continuous liquid phase [1-3]. Figure 21.1 shows the two main types of double emulsions water-in-oil-in-water (W/O/W) emulsions, in which a water-in-oil (W/0) emulsion is dispersed in an aqueous phase (Figure 21.1a) and oil-in-water-in-oil (O/W/O) emulsions, in which an oil-in-water (0/W) emulsion is dispersed in an oil phase (Figure 21.1b). Usually, both hydrophilic and lipophilic surfactants are required to stabilize these multilayered dispersions. 

The second stage of the process disperses the primary emulsion in an aqueous phase. A high-HLB (9-11) surfactant is dissolved in the external phase. The primary emulsion is then added to the surfactant solution and mixed. The method and intensity of mixing are chosen to achieve maximum dispersion with minimal rupture of multiple-emulsion droplets. The resultant multiple-emulsion preparation usually contains two types of droplets (Fig. 1). Although preparations of multiple emulsions usually contain both types of droplets, the relative amount of each type is dependent on the method of preparation and the surfactant at the OAV interface (Florence and Whitehill, 1981). 

Multiple emulsions are emulsion systems in which the disperse phase contains dispersed droplets of the external phase. Water-in-oil-in-water (W/O/W) type multiple emulsions are oil-in-water emulsions in which the dispersed oil drops themselves contain smaller dispersed aqueous droplets. These systems were observed as long ago as 1890 [136] but there has been increased interest recently in the use of W/O/W emulsions in such diverse fields as the separation of hydrocarbons [137], treatment of waste water [138], immobilization of enzymes [139], prolongation of drug release [140], and the treatment of drug overdosage [141]. O/W/O emulsions can also be formed. Two recent reviews have dealt with the topic of multiple emulsions, their preparation, pharmaceutical uses and stabilization [142, 143]. 

A double (multiple or complex) emulsion is an emulsion in an emulsion (Garti, 1997). Two main types of double emulsions can be distinguished water-in-oil-in-water (W/O/W) and oil-in-water-in-oil (OAV/O). A W/OAV emulsion consists of water droplets dispersed within larger oil droplets, which are themselves dispersed in an aqueous continuous phase. In an OAV/O emulsion, larger water droplets enclosing smaller oil droplets are dispersed in a continuous oil phase. W/O/W emulsions are more common than O/W/O emulsions. Other types of double emulsions such as oil-in-water-in-water (Kim et al., 2006) and ethanol-in-oil-in-water (Nakajima et al., 2003), have also been prepared and investigated. 

Emulsions in which water is the internal dispersed phase are termed water-in-oil emulsions (W/O), whereas emulsions in which oil is the dispersed phase and water is the continuous phase are known as oil-in-water (0/W) emulsions. More complex systems, in which one emulsion is further dispersed into another continuous phase, are called double emulsions, multiple emulsions, or emulsified emulsions [13-21] (Eig. 1). Two main types of double emulsions have been carefully studied W/O/W and O/W/O double emulsions. The average inner droplet size of the W/O emulsion in the double emulsion is usually smaller than 0.5 xm that of the outer, external double emulsion is quite large and often exceeds 20 qm. 

Nevertheless, a closer look at the conductivity value indicates the presence of multiple emulsions in B and C, the so-caUed abnormal zones, where there is a conflict between the composition and formulation effects. For instance, in the region a multiple w/OAV emulsion is found. In this case, the composition determines what is the main or outer (OAV) emulsion, whereas the formulation induces the secondary droplet-in-drop (w/O) inner emulsion. A similar situation, but with oAV/O multiple emulsions, is found in the B region. The relative amounts of these two emulsion types depend on the emulsification process, particularly on the way the formulation and composition are varied during the stirring. 

The term multiple emulsion describes a w/o emulsion ia an o/w emulsion. Eor example, when a w/o emulsion is added to water, no dispersion is expected unless the aqueous phase is fortified with a suitable emulsifier. The resultiag dispersioa may thea be a blead of a w/o and an o/w emulsion, or it may be a multiple emulsion of the w/o/w type. In this latter case, the initial w/o emulsion becomes the internal phase of the final product. Generally, these preparations are not very stable unless they are produced under rigidly controlled conditions (32,39,40). 

---