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.

Another Move towards Bicalutamide Dissolution and Permeability Improvement with Acetylated β-Cyclodextrin Solid Dispersion

“…Notably, a more pronounced shift of the dehydration peak in Ac-β-CD (T max = 54.2 ± 0.2 • C, T onset = 29.4 ± 0.2 • C) to the higher temperatures in the ground complex (T max = 57.4 ± 0.2 • C, T onset = 28.7 ± 0.2 • C) as compared to physical mixture (T max = 53.5 ± 0.2 • C, T onset = 30.4 ± 0.2 • C) can be attributed to the stronger interaction of BCL with the CD cavity in the complex. The endothermic melting peak at T max = 196.0 ± 0.2 • C (T onset = 193.9 ± 0.2 • C) in raw BCL (form I as was stated in [8]) is very close to the ground sample (BCL_gr) (T max = 194.6 ± 0.2 • C, T onset = 192.9 ± 0.2 • C) and maintaining the crystallinity. In the physical mixture with Ac-β-CD, the peak maximum (T max = 191.9 • C ± 0.2 • C) was broadened: T onset = 185.7 ± 0.2 • C instead of 193.9 ± 0.2 • C for the pure BCL sample.…”

“…The poor solubility of BCL in an aqueous solution was estimated elsewhere [ 4 , 5 , 8 ] earlier. Moreover, several attempts to improve the solubility have been undertaken (see the Introduction section).…”

“…In the next step, we compare the BCL permeability coefficient measured in the present study in the Franz cell through the cellulose membrane with the one evaluated across the PermeaPad barrier (biomimetic lipophilic barrier based on the liposome layer on the support sheet) in our earlier work [ 8 ]. P app (cellulose membrane) was shown to be 3.6-fold higher than P app (PermeaPad), obviously due to the significant resistance of the lipophilic layer of the barrier.…”

“…On the assumption of the UV spectrum's sensitivity to the dielectric properties of the dissolution medium [45] and the lower dielectric constant of CD as compared to water, the shift of λ max in the CD solutions is expected and approved for the formation of the complex. For the sake of comparison, the BCL absorption spectra in n-hexane (non-polar solvent) and ethanol, taken from our previous study [8], are also illustrated in Figure S1. Markedly, the shapes of all of the BCL absorption spectra were similar in all of the considered media.…”

“…An analysis of the available literature sources showed that the BCL solubility was improved 2-fold by β-cyclodextrin inclusion com- The extremely poor aqueous solubility of bicalutamide has been recognized in the literature as being approximately 8.85 mg•L −1 [4], 3.7 µg•mL −1 [5], and less than 5 mg•L −1 [6]. In addition, in our previous studies, it was estimated to be 8.1 × 10 −6 M, 1.30 × 10 −5 M, and 1.64 × 10 −5 M in water (25 • C, 35 • C, and 40 • C, respectively) [7,8], 1.44 × 10 −5 M (buffer pH 7.4, 25 • C) [9]. The pK a value of BCL equal to 11.49 (calculated by ACD/LABS) implies that the solubility in aqueous media is independent of pH in the biologically relevant region.…”