Volkova Tatyana V, Simonova Olga R, Perlovich German L
G.A. Krestov Institute of Solution Chemistry RAS, 153045 Ivanovo, Russia.
Pharmaceutics. 2022 Mar 18;14(3):674. doi: 10.3390/pharmaceutics14030674.
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.
首次测定了抗雄激素药物比卡鲁胺（BCL）的药理学相关物理化学性质。通过摇瓶法在293.15 - 313.15 K的温度范围内测定了其在水溶液、正辛醇、正己烷和乙醇中的溶解度。结果表明该化合物在水介质和正己烷中溶解度较差；同时，发现在醇类中的溶解度明显更高。确定了以下摩尔溶解度顺序：乙醇＞正辛醇＞水≈正己烷。溶解度与范特霍夫方程和阿佩尔布拉特方程相关。对汉森溶解度参数以及霍夫蒂泽尔和范克雷维伦的原子基团贡献法的评估表明与实验数据一致，且比卡鲁胺具有良好的潜在吸附性。在热力学方法的框架内测量并讨论了1-辛醇/水和正己烷/水两相体系中分配系数的温度依赖性。从分配实验确定的∆logD参数清楚地表明了该化合物在生物介质中亲脂性传递途径的偏好。基于本研究的溶解度和分配结果以及先前发表的升华特性进行了全面的热力学分析。为此，鉴于溶质 - 溶剂相互作用，计算并讨论了溶解、溶剂化和转移过程的热力学参数。测量了BCL通过PermeaPad屏障的渗透速率，并与PAMPA渗透率进行了比较。
