Micellar solubilization

Micellar solubilization

Micelles can be used to increase the solubility of materials that are normally insoluble or poorly soluble in the dispersion medium used. This phenom-enon is known as solubilization, and the incorporated substance is referred to as the solubilizate. For example, surfactants are often used to increase the solubility of poorly soluble steroids. The location, distribution, and orienta-tion of solubilized drugs in the micelles influence the kinetics and extent of drug solubilization. These parameters are determined by the molecular loca-tion of the interaction of drugs with the structural elements or functional groups of the surfactant in the micelles.

1. Factors affecting the extent of solubilization

Factors affecting the rate and extent of micellar solubilization include the nature of surfactants, the nature of solubilizates, temperature, and pH.

1. Nature of surfactants: Structural characteristics of a surfactant affect its solubilizing capacity because of its effect on the solubiliza-tion site within the micelle. In cases where the solubilizate is located within the core or deep within the micelle structure, the solubili-zation capacity increases with increase in alkyl chain length. For example, there was an increase in the solubilizing capacity of a series of polysorbates for selected barbiturates as the alkyl chain length was increased from C₁₂ (polysorbate 20) to C₁₈ (polysorbate 80).

An increase in the alkyl chain length increases the hydrophobicity of the core and micellar radius, reduces pressure inside the micelle, and increases the diffusive entry of the hydrophobic drug into the micelle. In addition, the solubilization of the poorly soluble drug tropicamide increased with increase in the oxyethylene content of poloxamer. On the other hand, an increase in the ethylene oxide chain length of a polyoxyethylated nonionic surfactant led to an increase in the total amount solubilized per mole of surfactant because of the increasing number of micelles. Thus, the effect of increase in the number of micelles of the same (smaller) size can be very different than increase in the size of micelles.

2. Nature of solubilizate (drug being solubilized): The location of solu-bilizates in the micelles is closely related to the chemical nature of the solubilizate. In general, nonpolar, hydrophobic solubilizates are local-ized in the micellar core. Compounds that have both hydrophobic and hydrophilic regions are oriented with the hydrophobic group facing or in the core and the hydrophilic or polar groups facing toward the sur-face. For a hydrophobic drug solubilized in a micelle core, an increase in the lipophilicity or the lipophilic region or surface area of the drug leads to solubilization near the core of the micelle and enhances drug solubility.

Unsaturated compounds are generally more soluble than their satu-rated counterparts. Solubilizates that are located within micellar core tend to increase the size of the micelles. Micelles become larger not only because their core is enlarged by the solubilizate but also because the number of surfactant molecules per micelle increases in an attempt to cover the swollen core.

3. Effect of temperature: In general, the amount of the drug solubilized increases with an increase in temperature (Figure 10.5). The effect is particularly pronounced with some nonionic surfactants, where it is a consequence of an increase in the micellar size with increasing temperature.

4. Effect of pH: The main effect of pH on solubilizing ability of non-ionic surfactants is to alter the equilibrium between ionized and unionized drugs. The overall effect of pH on drug solubilization is a function of proportion of ionized and unionized forms of the drug in solution and in micelles, which is determined by (1) the pK_a value of the ionizable functional group(s), (2) the solubility of the ionized and unionized forms in the solution, and (3) the solubilization capacity of the micelles for the ionized and union-ized forms. Generally, the unionized form is the more hydrophobic form and is solubilized to a greater extent in the micelles than the ionized form.

Figure 10.5 Effect of temperature and surfactant type on the micellar solubilization of griseofulvin and hexocresol. (Modified from Bates, T.R, Gilbaldi, M. and Kanig, J.I. J. Pharm. Sci., 55, 191, 1966. With Permission.)

2. Pharmaceutical applications

Several insoluble drugs have been formulated by using micellar solubiliza-tion. For example:

·           Phenolic compounds, such as cresol, chlorocresol, and chloroxylenol, are solubilized with soap to form clear solutions for use as disinfectants.

·           Polysorbates have been used to solubilize steroids in ophthalmic formulations.

·           Polysorbate are used to prepare aqueous injections of the water-insoluble vitamins A, D, E, and K.

·           Nonionic surfactants are efficient solubilizers of iodine.

3. Thermodynamics/spontaneity

Micellar solubilization involves partitioning of the drug between the micel-lar phase and the aqueous solvent. Thus, the standard free energy of solubi-lization, ∆G_s, can be computed from the partition coefficient, K, of the drug between the micelle and the aqueous medium:

∆G_s = −RT In K              (10.1)

where:

R is the gas constant

T is the absolute temperature

Change in free energy with micellization can be expressed in terms of the change in enthalpy (∆H_s) and entropy (∆S_s) as:

∆G_s = ∆H_s − T ∆S_s                 (10.2)

Thus,

∆H _s − T∆ S_s = −RT In K

Or,

In K = − − ∆Hs/R ⋅ 1/T + constant

where the constant is ∆S_s/R, assuming that the change in entropy from micellization is constant. Thus, experimental determination of enthalpy of micellization can be a useful tool to predict ∆G_s, which, in turn, indicates whether micellar incorporation of a drug would be spontaneous. When ∆G_s is negative, solubilization process is spontaneous. When ∆G_s is positive, solubilization does not occur.

Example 1: Given ∆H_s = 2830 cal/mol and ∆S_s = −26.3 cal/K mol, does ammonium chloride spontaneously transfer from water to micelles?

 ∆G_s = ∆H_s − T∆ S_s = 2830 cal/mol − (298K)( − 26.3 cal/kmol)

which is positive, indicating that micellar solubilization (transfer) would not occur.

Example 2: Given ∆H_s = −1700 cal/mol and ∆S_s = 2.1 cal/K mol, does amobarbital spontaneously transfer from water to a micellar solution (sodium lauryl sulfate, 0.06 mol/L)?

∆G_s = ∆H_s − T∆ S_s = 1700 cal/mol − (298K)( − 2 .1 cal/kmol) = −2326 cal/mol

which is negative, indicating that micellar solubilization (transfer) would indeed spontaneously occur.