Solubilized systems solubilizate

A preferred location of the solubilizate molecule within the micelle is largely dictated by chemical structure. However, solubilized systems are dynamic and the location of molecules within the micelle changes rapidly with time. Solubilization in surfactant aqueous systems above the critical micelle concentration offers one pathway for the formulation of poorly soluble drugs. From a quantitative point of view, the solubilization process above the CMC may be considered to involve a simple partition phenomenon between an aqueous and a micellar phase. Thus the relationship between surfactant concentration Cm and drug solubility Ctot is given by Eq. (3). 

Ternary systems are encountered in pharmacy mainly as emulsifier-oil-water systems in emulsions or as surfactant-solubilizate-water systems in the formulation of solubilized systems. Phase equilibria within ternary systems are most conveniently represented by a triangular phase diagram which delineates the phase regions enabling the formulator to select suitable combinations of the three components to produce stable emulsions or clear isotropic solubilized systems. 

As discussed in Chapter 2, liquid crystalline regions such as the neat and middle phases formed in concentrated surfactant solutions are capable of incorporation of solubilizates. The ternary systems so formed represent a type of solubilized system although such systems, being anisotropic, are not strictly in accordance with the definition of a solubilized system proposed above. Relatively few studies of these systems have been reported and we shall in this chapter concentrate exclusively on solubilization within the micellar, L, and the reverse micellar, L2, isotropic regions. 

The study of solubilized systems must obviously start with the determination of the concentration of solubilizate which can be incorporated into a given system with the maintenance of a single isotropic solution. This saturation concentration of solubilizate for a given concentration of surfactant is termed the maximum additive concentration (MAC). 

Phase diagrams. Solubilized systems contain at least three components, solubilizate, solvent, and surfactant. The amount of information one can obtain from a solubility curve is limited, but the system can be completely described at a given temperature and pressure by a ternary or quaternary phase diagram (see Chapter 2). 

In solubilized systems in which the solubilizate has a significant water solubility it is of interest to know not only the distribution ratio of solubilizate between the micelles and water under saturation conditions but also at varying degrees of saturation of the system with solubilizate. Such information cannot, of course, be obtained using the solubility methods discussed in Section 5.2.1. A dialysis technique has been described by Patel and Kostenbauder [32] and with various modifications has become a widely used technique [33-41]. In principle, the surfactant solution is separated from an aqueous solution of the solubilizate by a membrane permeable to solubilizate but not to micelles. In a typical dialysis cell the membrane is clamped between two Perspex half cells of approximately 150cm capacity (see Fig. 5.2). Provision is made for stirring and pH control if... 

Gel filtration techniques were first applied to solubilized systems by Herries et al. [57] and Borgstrom [58]. A development of this technique [59-64] involves tail analysis of the elution curves to obtain information not only about the elution behaviour of the solubilizates but also of the micelles themselves. Fig. 5.4 shows a typical elution curve of methylparaben solubilized in solutions of dodecyl-hexaoxyethylene glycol monoether, Ci2E6 The heights of the plateaux (S)t and (Z>)t correspond to the concentrations of C12E6 methylparaben, respectively, in the original sample. (D)m and (D)f are the concentrations of methylparaben solubilized in the micellar phase and of free methyl paraben in the aqueous phase, respectively. The low plateaux of the elution curve of corresponds to the... 

A micellar isolation method using an analytical ultracentrifuge and so avoiding the inherent errors associated with the use of membranes in the dialysis and ultrafiltration techniques, has been proposed by Park and Rippie [70]. In principle the solubilized systems are centrifuged under selected conditions such that about 40 % separation of micelles is achieved. By assuming that the apparent partition coefficient is independent of surfactant concentration, equations are presented whereby the distribution of the solubilizate can be calculated from analysis of the upper and lower portions of the contents of the centrifuge tube. 

Early workers examined the effect of phenol on various solubilizates [3,170]. Weicherz [171,172] showed that certain toluene-sodium oleate-water mixtures only formed a stable solubilized system if phenol was added. The addition of mono- and poly-hydroxyalcohols at concentrations of 5 % enhanced the solvent powers of several solubilizates with respect to the dye, yellow AB. Increasing the solubilizing powers of a surfactant has been termed a synergistic effect and decreasing them an antigistic effect. 

Thus far only processes involving motion of the surfactant as a whole have been mentioned. Other processes may occur in micellar solutions internal motion of the surfactant alkyl chains within the micelles exchange of cormterions between free and micelle-bound states and fast changes of micelle shape, among others. Also in the case of solubilized systems, i.e., micellar solutions that have solubilized compounds that are sparingly soluble in water, the solubilizate may exchange between micelles and the intermicellar solution. The dynamics of the exchange of counterions and of solubilizates are reviewed later. The dynamics of internal motions of the surfactant alkyl chains are not dealt with in this chapter, but some information and references can be found in Chapter 5, Section V. Some information on the fluctuations of micelle shapes can be found in Chapter 1, Section III.B. 

Solubilized systems refer to surfactant solutions in which the micelles have solubilized compounds (solubilizates) that are generally poorly soluble in water. Most studies address the rate constants for the exchange of the solubilizate. A few studies examine the effect of solubilizate other than cosrufac-tants on the surfactant exchange and micelle forma-tion/breakdown. 

Generally, solubilization occurs spontaneously when the pure solubilizate contacts the solution of reversed micelles. Often, vigorous stirring consistently reduces the time necessary to obtain complete solubihzation and thermodynamically stable systems. 

A nonpolar solubilizate such as hexane penetrates deeply into such a micelle, and is held in the nonpolar interior hydrocarbon environment, while a solubilizate such as an alcohol, which has both polar and nonpolar ends, usually penetrates less, with its polar end at or near the polar surface of the micelle. The vapor pressure of hexane in aqueous solution is diminished by the presence of sodium oleate m a manner analogous to that cited above for systems in nonpolar solvents. A 5% aqueous solution of potassium oleate dissolves more than twice the volume of propylene at a given pressure than does pure water. Dnnethylaminoazobenzene, a water-insoluble dye, is solubilized to the extent of 125 mg per liter by a 0.05 M aqueous solution of potassium myristate. Bile salts solubilize fatty acids, and this fact is considered important physiologically. Cetyl pyridinium chloride, a cationic salt, is also a solubilizing agent, and 100 ml of its A/10 solution solubilizes about 1 g of methyl ethyl-butyl either m aqueous solution. 

Two models for micelle structure were identiLed in their studies (Xing and Mattice, 1998). In analogy with the structural models for systems involving low molecular weight surfactants, two kinds of aggregates of spherical shape can be pictured, depending on how the solubilizates are located inside the block copolymer micelles. Solubilization takes places in two steps in the Xing and Mattice s simulations (1998). 

The very complex variation of the amount solubilized, as well as physico-chemical properties, with chemical structure of solubilizate and surfactant as well as with surfactant concentration cannot be adequately discussed solely in terms of the energetical conditions of the solubilizate in the micelles. Thus one should also consider the conditions in the phase which separates out at the solubilization limit this is in most cases a liquid crystalline phase. A fundamental basis for a proper understanding of solubilization in surfactant systems is, therefore, a detailed information on phase equilibria in three-component systems surfactant-solubilizate-water. Due in particular... 

In our laboratories, extensive use has been made of vapor pressure (14-18) and membrane methods ( 2, 3, 19, 20) to Infer thermodynamic results for ternary aqueous systems containing an ionic or a nonionic surfactant and an organic solute. The most precise solubilization measurements ever reported have been obtained with an automated vapor pressure apparatus for volatile hydrocarbon solutes such as cyclohexane and benzene, dissolved In aqueous solutions of sodium octylsulfate and other Ionic surfactants (15, 16). A manual vapor pressure apparatus has been employed to obtain somewhat less precise results for solutes of lower volatility (17, 18). Recently, semi-equilibrium dialysis (19, 20) and MEUF (2) methods have been used to investigate solute-surfactant systems in which the organic solubilizates are too involatile to study by ordinary vapor pressure methods. 

N.m.r. and e.s.r. techniques similar to those used for the determination of the location and environment of solubilizates in micellar systems have also been employed in investigations of solubilization by lipid micelles and of protein-substrate interactions (McDonald and Phillips, 1967 Meadows et al., 1967 Spotswood et al., 1967 Chapman, 1968 Penkett et al., 1968 Mildvan and Weiner, 1969 Raftery et al., 1969 Roberts et al., 1969a, b Rosenberg et al., 1969 Small et al., 1969). 

The most important property of micelles in aqueous or nonaqueous solvents is their ability to dissolve substances that are insoluble in the pure solvent. In aqueous systems, nonpolar substances are solubilized in the interior of the micelles, whereas polar substances are solubilized in the micellar core in nonaqueous systems. This process is called solubilization. It can be defined as the formation of a thermodynamically stable isotropic solution with reduced activity of the solubilized material (8). It is useful to further differentiate between primary and secondary solubilization. The solubilization of water in tetrachloroethylene containing a surfactant is an example of primary solubilization. Secondary solubilization can be considered as an extension of primary solubilization because it refers to the solution of a substance in the primary solubilizate. 

Solubilization can be defined as the preparation of a thermodynamically stable isotropic solution of a substance normally insoluble or very slightly soluble in a given solvent by the introduction of an additional amphiphilic component or components. The amphiphilic components (surfactants) must be introduced at a concentration at or above their critical micelle concentrations. Simple micellar systems (and reverse micellar) as well as liquid crystalline phases and vesicles referred to above are all capable of solubilization. In liquid crystalline phases and vesicles, a ternary system is formed on incorporation of the solubilizate and thus these anisotropic systems are not strictly in accordance with the definition given above. 

The solubilizing capacity for a given surfactant system is a complex function of the physicochemical properties of the two components which, in turn, influence the location or sites where the drug is bound to the micelle. The molar volume of the solubilizate together with its lipophilicity are important factors, the former reducing and the latter increasing solubilization. ... 

It appears that for each snrfactant system, AG° is a linear fnnction of the number of carbon atoms of the solubihzate see, for example, the work by DeLisi and co-workers who have stndied alcohol solubilization in SDS, dodecyltrimethylammonium bromide, and dodecyldimethylamine oxide.In this work we prefer to plot AG" as a fimction of the niunber of CH2 groups of the solubilizate. Tables 6.2 through 6.6 contain data for several homologous series in anionic, cationic, and nonionic surfactants, and on this basis the following relationship has been tested ... 

Solubilization is distinguished from emulsification (the dispersion of one liquid phase in another) by the fact that in solubilization, the solubilized material (the solubilizate ) is in the same phase as the solubilizing solution and the system is consequently thermodynamically stable. 

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