Chapter 2

What is an emulsion?

An emulsion is a biphasic, metastable coarse dispersion of two immiscible materials, usually liquids (typically oil and water), that produces a semisolid (Sarker, 2008). A spherical droplet (dispersed phase) is distributed in a dispersion medium (or continuous phase). This can occur for more than a few seconds only if the droplet is covered (Figure 2.1) with a layer of emulsifier molecules (monolayer). The particle size is variable and usually covers the range 5–10 nm (micelle), 20–50 nm (microemulsion or swollen micelle), 100 nm (nanoemulsion), 50–200 nm (solid lipid nanoparticle, SLN) to a very large 500–5000 nm (coarse emulsion) (Becher, 2001). At sizes above 5 microns, dispersed droplets are relatively unstable and are not suitable for injection (as the capillary diameter of vasculature may be as small as 20–30 μm), but they may be used externally for topical preparation. Still larger droplets lack usefulness in pharmacy as they are susceptible to creaming, followed by increased rates of coalescence (Sarker et al., 1998a,b).

Figure 2.1 The anatomy of the ‘course emulsion’, often referred to simply as the ‘emulsion’. Course emulsions typically have diameters larger than 500 nm, usually 1–2 μm. HLB, hydrophile–lipophile balance

Figure 2.1 shows the three basic forms of coarse emulsion. Emulsions that are primarily composed of spherical droplets can be defined by a phase volume (). Particles remain spherical up to a maximum of 0.74; in this case, spheroids assume a polyhedral appearance and are present as a highly concentrated emulsion. Upon loss of spherical shape, many of the droplets undergo coalescence or phase inversion. In pharmacy and cosmetology, emulsions are frequently used to place the apolar drug dose in a given specific volume. These are usually oil-in-water (O/W) emulsions. The oil and water form the dispersion phase (dependant on the emulsifier hydrophile–lipophile balance (HLB) or a mix of emulsifiers and overall HLB). The form and size of the emulsifier alkyl chain determine both its HLB and thus the type of emulsion which forms. The phase that forms the dispersed or continuous phase also depends on the pharmaceutical formulation and temperature.

Given appropriate mechanical energy input, dispersed droplets of oil (or water) form emulsions. These emulsions may be called creams, ointments, liniments (balms), pastes, bases or occlusive films or liquids, depending mostly on their oil and water proportions and their use. Topical dosage forms (e.g. creams and ointments) are used on the surface of the skin, transdermally, vaginally or rectally. Liquid-like () emulsions can also be used orally or injected via various routes (typically intravenously or intramuscularly). Frequently encountered topical emulsions include acyclovir (cold sore) cream, hydrocortisone cream and clotrimazole vaginal antifungal cream.

A micelle (see Figure 1.2) is a self-assembled emulsifier-based particle (see Sections 2.1.1, 4.3, 5.2.5, 7.2, 7.4, 8.3, 12.2 and 12.4), used to deliver high log apolar drugs such as miconazole (Sarker et al., 1995a,b; Sarker, 2005a,b, 2006a), which is used in the treatment of thrush. Micelles form spontaneously and are thermodynamically stable; like microemulsions, they can only form in the presence of polymeric or simple emulsifiers. A ‘swollen micelle’ or microemulsion (Figure 2.1) is used to deliver apolar drugs in ‘solution’ for ocular therapy (e.g. anaesthesia) and to encapsulate vaccines. Typically, the emulsions are nanoemulsions of soybean (soya) oil, with particle diameters of 20–50 nm. They form spontaneously but require two or more emulsifiers of varying sizes and much higher concentrations of surfactant (10–25% w/v emulsifier) than for conventional coarse emulsions. They can be manufactured using synthetic or naturally occurring emulsifiers such as bile salts (sodium deoxycholate, taurocholate). Microemulsions, having a lipid-filled core, can thus be used to fabricate SLNs.

Nanoemulsions (Sarker et al., 1999; Sarker, 2005a,b, 2006a; see Figure 1.2) are smaller versions of coarse emulsions and are phenomenologically unrelated to microemulsions. They are typically 50–400 nm in diameter and are limited to a minimum size of about 40 nm, due to surface coverage. They are produced by extremely high-shear mixing of dilute emulsion premixes using strongly surface-stabilising mixtures of lipids, low-molecular-weight (LMW) emulsifiers and polymeric emulsifiers (Sarker, 2005b, 2006a). Some types of nanoemulsion are currently under study for their use against HIV-1 and TB pathogens (Richards et al., 2004).

Liposomes (see Figure 1.2) represent another form of lipid encapsulation (Sarker, 2009a). They consist of a bilayered envelope (lamella, bilayer, leaflet) with an aqueous core. Since a micelle or liposome is a lipid (apolar) based structure and is made of ‘fat’, solubilisation of the drug in an alkyl chain-rich environment is analogous to a form of emulsification. In this book, the term ‘emulsification’ is used in the ‘true sense’ but also to infer encapsulation and lipid solvation. Some unusual forms of emulsion can be fabricated using liposomes. One such example is the use of liposomes (a form of dispersion) to fabricate multiple emulsion droplets (Wang et al., 2010). In this case, their use as an immunological adjuvant induces the production of cytotoxic T-lymphocytes raised against an HIV envelope antigen (Richards et al., 2004).

Such fascinating complexity is more often exploited in a simpler form, for example as:

• Vesicles or liposomes.

Many modified liposomes are currently under investigation (Sarker, 2009a). Basic types include:

• Small unilamellar types (SUV), large unilamellar types (LUV) and multilamellar types (MLV). Depending on the type of component used in the fabrication, these are routinely known as:
  • proteoliposomes: constituted with antigens;
  • chitosomes: constituted with chitosan;
  • niosomes: constituted with nonionic surfactants;
  • dermosomes: constituted with phospholipids and cholesterol;
  • virosomes: constituted with viral antigens;
  • polymersomes: constituted with polymers.

In any case, the three basic components of all dispersions (including liposomes) based on oil are water, oil and emulsifier(s), but other components may be included, such as drug, antioxidant and preservatives.

Droplets which make up emulsions (creams, lotions, ointments, nano- or microemulsions) are sometimes referred to as particles (see Figure 1.2 and Figure 2.1). These particles are separated by a thin liquid film (TLF) or lamella. The lamella terminates at an intersection called the Plateau border (or a node where Plateau borders meet). The TLF, its surface chemistry and its mechanical properties play an often understated role in determining suspension and emulsion metastability (see Sections 2.2.1, 3.2, 3.3 and 14.3).

One prerequisite for the formation of any emulsion is that it makes use of an emulsifying agent to form particles; without this, coalescence and liquid droplet fusion are inevitable. Even with SLNs (solid emulsions), initial formation is impossible without the presence of an emulsifier (Sarker, 2012a). The dispersed phase in continuous phases (dispersion medium) determines the nomenclature. There are three basic forms of coarse emulsion: O/W, water-in-oil (W/O) and multiple (e.g. water-in-oil-in-water). The most common forms in pharmacy are O/W emulsions, particularly for parenteral administration; W/O forms do exist, but they are normally reserved for dermal applications. Use of emulsions can be for taste-masking purposes but is usually for solubilisation of apolar moieties. For all emulsions, the increase in energy associated with dispersal makes the system thermodynamically unstable; however, the discrepancy is filled by a monolayer or multilayer of adsorbed material (i.e. surfactant/emulsifier, hydrocolloids, finely divided solids (see Section 2.3.2)).

True colloids (microemulsions, SLNs, micelles) are defined by a nanometre size, by being thermodynamically stable and by spontaneous formation. Coarse emulsions are not colloids, although they may have components which are colloidal (e.g. adsorbed macromolecules), but rather are dispersions (mostly opaque), generally being of a micrometre size (or bigger) range. Emulsions typically have higher surface free energy than microemulsions (swollen micelles) and cannot be reconstituted.

The use of emulsions for creams, ointments and parenteral (injectable) medicines is discussed at length in Chapters 5 and 7. One dramatically expanding area of emulsion use is as vaccines (Richards et al., 2004), or rather as adjuvants to promote/enhance immunological effect. Examples of such uses are presented in Table 2.1.

Table 2.1 Emulsions used as vaccines and vaccine aids

Emulsion vaccines frequently use biocompatible fatty acids and lecithin-based polymer derivatives as emulsifiers, such as Transcutol P (Gattefossé), Kolliphor EL (BASF) or Miranol C2M (Rhodia). Therapeutics of this type are not new, since the first therapeutic based on oil, which used cyclosporine and Cremophor, was approved by the US Food and Drug Administration (FDA) in the 1980s. Some interesting examples of in-development (Table 2.1) and developed vaccine emulsions are presented in Figure 2.2.

Figure 2.2 Use of...