Physicochemical Profile of Antiandrogen Drug Bicalutamide: Solubility, Distribution, Permeability

Abstract

The pharmacologically relevant physicochemical properties of the antiandrogen drug bicalutamide (BCL) have been determined for the first time. Solubility in aqueous solution, 1-octanol, n-hexane, and ethanol was measured by the shake flask method in the temperature range of 293.15−313.15 K. The compound was shown to be poorly soluble in aqueous medium and n-hexane; at the same time, an essentially higher solubility in the alcohols was revealed. The following order of molar solubility was determined: ethanol > 1-octanol > water ≈ n-hexane. The solubility was correlated with the Van’t Hoff and Apelblat equations. Evaluation of the Hansen solubility parameters and the atomic group contribution approach of Hoftyzer and Van Krevelen demonstrated consistency with the experimental data and good potential adsorption of bicalutamide. The temperature dependences of the distribution coefficients in the 1-octanol/water and n-hexane/water two-phase systems were measured and discussed in the framework of the thermodynamic approach. The ∆logD parameter determined from the distribution experiment clearly demonstrated the preference of the lipophilic delivery pathways for the compound in the biological media. The overall thermodynamic analysis based on the solubility and distribution results of the present study and the sublimation characteristics published previously has been performed. To this end, the thermodynamic parameters of the dissolution, solvation, and transfer processes were calculated and discussed in view of the solute-solvent interactions. The permeation rate of BCL through the PermeaPad barrier was measured and compared with PAMPA permeability.

Keywords: Hansen parameter; bicalutamide; distribution coefficient; solubility; thermodynamic approach.

Figure 1

The structure of bicalutamide (BCL).

Figure 2

Bagley diagram for BCL. Red and blue dashed lines indicate the Breitkreutz [34] parameters for BCL and those parameters characteristic for the optimal absorption.

Figure 3

Temperature dependences of the BCL solubility in the investigated solvents (mole fraction scale).

Figure 4

Temperature dependences of the experimental apparent distribution coefficients of BCL in the 1-octanol/water (red color), n-hexane/water (blue color), and 1-octanol/n-hexane (green color) systems (mole fraction scale).

Figure 5

Enthalpy/entropy relationship for the transfer of BCL from water to 1-octanol (red circles) and n-hexane (blue triangles), and from n-hexane to 1-octanol (green squares): hypothetical transfer—the filled symbols; “real” transfer—the empty symbols. The isoenergetic curves of the function are marked by dotted lines.