R8

Wt % hydrophile

Figure 6.36 The Pluronic grid for (a) the poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) [Pluronic] series and (b) the poly(oxypropylene)-poly(oxyethylene)-poly(oxypropylene) [Pluronic R] series of block copolymers.

concentration is termed the maximum additive co„ce„tratio„ (MAC). The simplest method of determining the MAC is to prepare a series of vials containing surfactant solution of known concentration. Increasing amounts of solubil-isate are added and the vials are then sealed and agitated until equilibrium conditions are established. The maximum concentration of solubilisate forming a clear solution can be determined by visual inspection or from extinction or turbidity measurement on the solutions.

Solubility data are expressed as a solubility-concentration curve or as phase diagrams. The latter are preferable since a three-component phase diagram completely describes the effect of varying all three components of the system - namely, the solubilisate, the solubiliser and the solvent. The axes of the phase diagram form an equilateral triangle (see Fig. 6.37), each side of which is divided into 100 parts to correspond to percentage composition.

A typical phase diagram of a solubilised system is shown in Fig. 6.38. In solutions of high water content the oil is solubilised in the micelles of the nonionic surfactant Brij 97 (C18H35(OCH2CH2)10OH), forming an isotropic micellar solution (often referred to as the L1 region). When the concentration of the oil is increased, stable oil-in-water emulsions may be formed, while an increase in the surfactant concentration results in the formation of the liquid crystalline regions, labelled middle and neat phases (see section 6.4). It is important in formulation to avoid boundary regions, as otherwise there is a danger of unwanted phase transitions.

6.6.2 Location of the solubilisate

The site of solubilisation within the micelle is closely related to the chemical nature of the solubilisate (see Fig. 6.39). It is generally accepted that nonpolar solubilisates (aliphatic hydrocarbons, for example) are dissolved in the hydrocarbon core of ionic and nonionic micelles. Water-insoluble compounds containing polar groups are orientated with the polar group at the core/surface interface of the

Figure 6.37 Three-component phase diagram. Point P represents a system of composition 20% A, 30% B and 50% C. Line CD represents the dilution of a mixture, originally containing 70% A and 30% B, with component C.

Brij 97

Neat ph^

Middle phase Gel

Isotropic micellar solution Water

Brij 97

Neat ph^

Oily isotropic phase

Mineral oil

Emulsoid Stable oil-in-water emulsion

Figure 6.38 Partial phase diagram for the Brij 97 (C18H35 (OCH2CH2)10OH)-water-mineral oil solubilised system.

Redrawn from R. Lachampt and R. M. Vila, Am. Perfum. Cosmet., 82, 29 (1967).

Oily isotropic phase

Mineral oil

Emulsoid Stable oil-in-water emulsion

Figure 6.38 Partial phase diagram for the Brij 97 (C18H35 (OCH2CH2)10OH)-water-mineral oil solubilised system.

Redrawn from R. Lachampt and R. M. Vila, Am. Perfum. Cosmet., 82, 29 (1967).

Figure 6.39 Schematic representation of sites of solubilisation depending on the hydrophobicity of the solubilisate. Completely water-insoluble hydrophobic molecules are incorporated in the micelle core (case 1); water-soluble molecules may be solubilised in the polyoxyethylene shell of a nonionic micelle (case 4); solubilisates with intermediate hydrophobicities (cases 2 and 3) are incorporated in the micelle with the hydrophobic region (black) in the core and the hydrophilic region (white) at the micelle/water interface. Redrawn from V. Torchilin, J. Control. Release, 73, 137 (2001).

Figure 6.39 Schematic representation of sites of solubilisation depending on the hydrophobicity of the solubilisate. Completely water-insoluble hydrophobic molecules are incorporated in the micelle core (case 1); water-soluble molecules may be solubilised in the polyoxyethylene shell of a nonionic micelle (case 4); solubilisates with intermediate hydrophobicities (cases 2 and 3) are incorporated in the micelle with the hydrophobic region (black) in the core and the hydrophilic region (white) at the micelle/water interface. Redrawn from V. Torchilin, J. Control. Release, 73, 137 (2001).

micelle and the hydrophobic group buried inside the hydrocarbon core of the micelle. In addition, solubilisation in nonionic poly-oxyethylated surfactants can occur in the polyoxyethylene shell (palisade layer) which surrounds the core. ^-Hydroxybenzoic acid, for example, is solubilised entirely within this region of the cetomacrogol micelle, whilst esters of ^-hydroxybenzoic acid are located at the palisade-core junction, with the ester group just within the core.

Solubilisates that are located within the micellar core increase the size of the micelles in two ways. Micelles become larger not only because their core is enlarged by the solubil-isate but also because the number of surfactant molecules per micelle (the aggregation number) increases in an attempt to cover the swollen core. Solubilisation within the palisade layer, on the other hand, tends not to alter the aggregation number, the increase in micellar size resulting solely from the incorporation of solubilisate molecules.

6.6.3 Factors affecting solubilisation Nature of the surfactant

Chain length of hydrophobe

It is difficult to generalise about the way in which the structural characteristics of a surfactant affect its solubilising capacity because this is influenced by the solubilisation site within the micelle. In cases where the solubilisate is located within the core or deep within the micelle structure, the solubilisation capacity increases with increase in alkyl chain length as might be expected. Table 6.10 clearly shows an increase of solubilising capacity of a series of polysorbates for selected barbiturates as the alkyl chain length is increased from C12 (Polysorbate 20) to C18 (Polysorbate 80). Similar effects have been noted for the solu-bilisation of barbiturates in polyoxyethylene surfactants with the general structure CH3(CH2)m(OCH2CH2)„OH with increasing alkyl chain length, m. There is a limit, however, to the improvement of solubilising capacity caused by increase of alkyl chain length in this way: an increase of m from 16 to 22, although producing larger micelles, does not result in a corresponding increase of solubilisation.19

Ethylene oxide chain length

The effect of an increase in the ethylene oxide chain length of a polyoxyethylated nonionic

Table 6.10 Solubilising capacity of polysorbates for the barbiturates at 30°Ca

Dmg

Surfactant

Solubility (mg drug per g surfactant)

Phenobarbital

Polysorbate 20

0 0

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