Hlb

Figure 7.13 Variation of mean globule size in a mineral oil-in-water emulsion as a function of the HLB of the surfactant mixtures present at a level of 2.5%. Surfactants: Brij 92-Brij 96 mixtures.

Source: P. Depraetre, M. Seiller, A. T. Florence and F. Puisieux (unpublished).

nonionic surfactants, an optimal HLB of between 7.5 and 8 is identified.

At the optimum HLB the mean particle size of the emulsion is at a minimum (Fig. 7.13) and this factor would explain to a large extent the stability of the system (see equations 7.1 and 7.2, for example).

Although the optimum HLB values for forming o/w emulsions are obtained in this way, it is possible to formulate stable systems with mixtures of surfactants well below the optimum. This is sometimes because of the formation of a viscous network of surfactant in the continuous phase. The high viscosity of the medium surrounding the droplets prevents their collision and this overrides the influence of the interfacial layer and barrier forces due to the presence of the adsorbed layer.

The HLB system has several drawbacks. The calculated HLB, of course, cannot take account of the effect of temperature or that of additives. The presence in emulsions of agents which salt-in or salt-out surfactants will respectively increase and decrease the effective (as opposed to the calculated) HLB values. Salting-out the surfactant (for example, with NaCl) will make the molecules less hydro-philic and one can thus expect a higher optimal calculated HLB value for the stabilising surfactant for o/w emulsions containing sodium chloride. Examples are shown in Fig. 7.14 in which the effects of NaCl and Nal are compared.

7.3.3 Multiple emulsions

Multiple emulsions are emulsions whose disperse phase contains droplets of another phase1,2 (Fig. 7.10). Water-in-oil-in-water (w/o/w) or o/w/o emulsions may be prepared, both forms being of interest as drug delivery systems. Water-in-oil emulsions in which a water-soluble drug is dissolved in the aqueous phase may be injected by the subcutaneous or intramuscular routes to produce a delayed-

action preparation, as to escape the drug has to diffuse through the oil to reach the tissue fluids. The main disadvantage of a w/o emulsion is generally its high viscosity, brought about through the influence of the oil on the bulk viscosity. Emulsifying a w/o emulsion using surfactants which stabilise an oily disperse phase can produce w/o/w emulsions with an external aqueous phase and lower viscosity than the primary emulsion. On injection, into muscle for example, the external aqueous phase dissipates rapidly, leaving behind the w/o emulsion. Nevertheless, bio-pharmaceutical differences have been observed between w/o and multiple emulsion systems. (Fig. 7.15)

Physical degradation of w/o/w emulsions can arise by several routes: (Fig. 7.16a):

• Coalescence of the internal water droplets

• Coalescence of the oil droplets surrounding them

• Rupture of the oil film separating the internal and external aqueous phases

Figure 7.14 The change in critical HLB values as a function of added salt concentration, where the salt is either NaCl or Nal. Results were obtained from measurements of particle size, stability, viscosity and emulsion type as a function of HLB for liquid paraffin-in-water emulsions stabilised by Brij 92-Brij 96 mixtures. Data from different experiments showed different critical values; hence, on each diagram hatching represents the critical regions while data points actually recorded are shown. Results in (a) show particle size and stability data; those in (b) show the HLB at transition from pseudoplastic to Newtonian flow properties (see section 7.3.10) and emulsion type (o/w2 w/o) transitions.

Reproduced from A. T. Florence, F. Madsen and F. Puisieux, J. Pharm. Pharmacol., 27, 385 (1975).

Figure 7.14 The change in critical HLB values as a function of added salt concentration, where the salt is either NaCl or Nal. Results were obtained from measurements of particle size, stability, viscosity and emulsion type as a function of HLB for liquid paraffin-in-water emulsions stabilised by Brij 92-Brij 96 mixtures. Data from different experiments showed different critical values; hence, on each diagram hatching represents the critical regions while data points actually recorded are shown. Results in (a) show particle size and stability data; those in (b) show the HLB at transition from pseudoplastic to Newtonian flow properties (see section 7.3.10) and emulsion type (o/w2 w/o) transitions.

Reproduced from A. T. Florence, F. Madsen and F. Puisieux, J. Pharm. Pharmacol., 27, 385 (1975).

Figure 7.15 Blood levels of (3 H)5-fluorouracil (5-FU) following intramuscular injection of (•) an aqueous solution, (□) a w/o emulsion prepared with hexadecane, and a w/o/w emulsion prepared with (A) isopropyl myristate or (■) hexadecane as the oil phase.

• Osmotic flux of water to and from the internal droplets, possibly associated with inverse micellar species in the oil phase

The external oil particles may coalesce with others (which may or may not contain internal aqueous droplets), as in route (a); the internal aqueous droplets may be expelled individually (routes b, c, d, e) or more than one may be expelled (route f), or less frequently they may be expelled in one step (route g); the internal droplets may coalesce before being expelled (routes h, i, j, k); or water may pass by diffusion through the oil phase, gradually resulting in shrinkage of the internal droplets (routes l, m, n). Figure 7.16 is oversimplified; in practice the number of possible combinations is large. Several factors will determine the breakdown mechanisms in a particular system, but one of the main driving forces behind each step will be the reduction in the free energy of the system brought about by the reduction in the interfacial area.

Mechanisms of drug release from multiple emulsion systems include diffusion of the drug molecules from the internal droplets (1), from the medium of the external droplets (2), or by mass transfer due to the coalescence of the internal droplets (3), as shown in Fig. 7.16(b)

Nonaqueous emulsions

Few studies have been carried out on non-aqueous emulsions, but these can be useful as topical vehicles or reservoirs for the delivery of hydrolytically unstable drugs. Systems such as castor oil or propylene glycol in silicone oil can be formulated using silicone surfactants; the HLB number clearly does not help in the formulation, especially if the continuous phase has low polarity. The key to stabilisation lies in the sufficient solubility of the emulsifier in the continuous phase.

Figure 7.16 (a) Possible breakdown pathways (see text) in w/o/w multiple emulsions (Whitehill and Florence). (From reference 1.) (b) Diagrammatic representation of mechanisms of drug release (see text). (From S. S. Davis, J. Clin. Pharm., 1, 11 (1976).) See text for explanation.

7.3.4 Microemulsions

Microemulsions consist of apparently homogeneous transparent systems of low viscosity which contain a high percentage of both oil and water and high concentrations (15-25%) of emulsifier mixture. They were first described by Schulman as disperse systems with spherical or cylindrical droplets in the size range 8-80 nm. They are essentially swollen micellar systems, but obviously the distinction between a swollen micelle and small emulsion droplet is difficult to assess.

Microemulsions form spontaneously when the components are mixed in the appropriate ratios and are thermodynamically stable. In their simplest form, microemulsions are small droplets (diameter 5-140 nm) of one liquid dispersed throughout another by virtue of the presence of a fairly large concentration of a suitable combination of surfactants. They can be dispersions of oil droplets in water (o/w) or water droplets in oil (w/o). An essential requirement for their formation and stability is the attainment of a very low interfacial tension y. Since microemulsions have a very large interface between oil and water (because of the small droplet size), they can only be ther-modynamically stable if the interfacial tension is so low that the positive interfacial energy (given by yA, where A is the interfacial area) can be compensated by the negative free energy of mixing AGm. We can calculate a rough measure of the limiting y value required as follows: A Gm is given by "T ASm (where T is the temperature), and the entropy of mixing (ASm) is of the order of the Boltzmann constant. Hence kBT = 4nr2y. Hence for a droplet radius r of about 10 nm, an interfacial tension of 0.03 mN m"1 would be required. The role of the surfactants in the system is thus to reduce the interfacial tension between oil and water (typically about 50 mN m01) to this low level.

Use of cosurfactants

With the possible exception of double alkyl chain surfactants and a few nonionic surfactants, it is generally not possible to achieve the required interfacial area with the use of a single surfactant. If, however, a second amphi-phile is added to the system, the effects of the two surfactants can be additive provided that the adsorption of one does not adversely affect that of the other and that mixed micelle formation does not reduce the available concentration of surfactant molecules. The second amphiphile is referred to as the cosurfactant.

The importance of the cosurfactant is illustrated in the following example. The interfacial tension between cyclohexane and water is approximately 42 mN m"1 in the absence of any added surfactant. The addition of the ionic surfactant sodium dodecyl sulfate (SDS) in increasing amounts causes a gradual reduction of y to a value of about 2 mN m 1 at an SDS concentration of 10"4 g cm"3. Further reduction of interfacial tension does not occur, since the cyclohexane/water interface is now saturated with SDS and any SDS added in excess of this limiting concentration forms micelles in the aqueous solution. Addition of 20% pentanol to the cyclohexane-water system in the absence of SDS reduces the interfacial tension to 10 mN m"1. It is then theoretically possible by the addition of SDS to achieve a negative interfacial tension at SDS concentrations below the level at which it forms micelles (the critical micelle concentration, cmc). The changes in interfacial tension occurring in this system are illustrated in Fig. 7.17. Although pentanol is not generally regarded as a surfactant, it has the ability to reduce interfacial tension by virtue of its amphiphilic nature (a short hydrophobic chain and a terminal hydrophilic hydroxyl group) and functions as the cosurfactant in this system. Its presence means that the SDS is now required to produce a much smaller lowering of the interfacial tension (10 mN m 1 rather than 42 mN m"1 in its absence) in order to produce a microemulsion.

The simplest representation of the structure of microemulsions is the droplet model in which microemulsion droplets are surrounded by an interfacial film consisting of both surfactant and cosurfactant molecules, as illustrated in Fig. 7.18. The orientation of the amphiphiles at the interface will, of course, differ in o/w and w/o microemulsions. As

Figure 7.18 Diagrammatic representation of microemulsion structures: (a) a water-in-oil microemulsion droplet; (b) an oil-in-water microemulsion droplet; and (c) an irregular bicontinuous structure.

shown in Fig. 7.18, the hydrophobic portions of these molecules will reside in the dispersed oil droplets of o/w systems, with the hydro-philic groups protruding in the continuous phase, while the opposite situation will be true of w/o microemulsions. For systems of known composition, an estimation may be made of the droplet radius r using r = 3$Csa0, where <p is the volume fraction of the disperse phase, Cs is the number of surfactant molecules per unit volume, and a0 is the surface area of a surfactant molecule at the interface. In practice not all of the surfactant can be assumed to be associated with the interface, and Cs is consequently seldom known with any certainty, although it is often assumed that the amount of surfactant in the continuous phase approximates to the surfactant cmc.

Whether the systems form o/w or w/o micro-emulsions is determined to a large extent by the nature of the surfactant. The geometry of the surfactant molecule is important. If the volume of the surfactant molecule is v, the cross-sectional area of its head group a, and its length l, then when the critical packing parameter v/al (see section 6.3.3) has values of between 0 and 1, o/w systems are likely to form, but when v/al is greater than 1, w/o microemulsions are favoured. Values of the critical packing parameter close to unity can result in the formation of a bicontinuous structure in which areas of water can be imagined to be separated by a connected amphiphile-rich interfacial layer as depicted in Fig. 7.18(c). Values of the parameters v, a and l can be readily estimated, but it should be noted that the critical packing parameter is based purely on geometric considerations. Penetration of oil and cosurfactant into the surfactant interface and hydration of the surfactant head groups will also influence the packing of the molecules in the interfacial film around the droplets. In many systems, inversion from w/o to o/w microemulsions can occur as a result of changing the composition or the temperature. In general, o/w micro-emulsions are favoured when small amounts of oil are present and w/o systems form in the presence of small amounts of water. Under such conditions the droplet model is a reasonable representation of the system. The structure of microemulsions containing almost equal amounts of oil and water is best represented by a bicontinuous structure.

A microemulsion formulation

A formulation of ciclosporin (Sandimmun Neoral, Novartis) incorporates the drug in a preconcentrate which forms a microemulsion on dilution in aqueous fluids.3,4 This formulation offers an alternative to the oil formulation of ciclosporin (Sandimmun) which in vivo would be emulsified by bile salts and pancreatic enzymes. The residence time of ciclosporin in the gastrointestinal tract is shorter and the rate of absorption is faster with the microemulsion formulation5 (Fig. 7.19).

W/o microemulsions incorporating medium-chain glycerides have been used to deliver calcein intraduodenally and produce significantly higher plasma levels of the drug compared to an aqueous formulation.6

7.3.5 Structured (semisolid) emulsions

In sections 7.3.1-7.3.4 we have considered only relatively simple dilute emulsions. Many pharmaceutical preparations, lotions or creams are, in fact, complex semisolid or structured systems which contain excess emulsifier over that required to form a stabilising mono-layer at the oil/water interface. The excess surfactant can interact with other components either at the droplet interface or in the bulk (continuous) phase to produce complex semisolid multiphase systems. Theories derived to explain the stability of dilute colloidal systems cannot be applied directly. In many cases the formation of stable interfacial films at the oil/water interface cannot be considered to play the dominant role in maintaining

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