Solubility and thermodynamic aspects of etonogestrel in several aqueous co-solvent solutions

Abstract

The current work was devoted to the investigation on equilibrium solubility, Hansen solubility parameter, solvation performance and dissolution thermodynamics of etonogestrel in binary aqueous blends of the cosolvents {n-propanol, N,N-dimethylformamide (DMF), ethanol or isopropanol} by experimentation and several mathematical relationships. The solubility determination was conducted under atmospheric pressure (101.2 kPa) from 278.15 to 323.15 K through the common shake-flask method. The maxima of etonogestrel solubility expressed in mole fraction scale at 323.2 K were observed as 8.713 × 10−3 for ethanol, 16.81 × 10−3 for n-propanol, 19.52 × 10−3 for isopropanol and 121.4 × 10−3 for DMF; while the minimum was 0.01477 × 10−3 for pure water at 278.15 K. The solubility performance of etonogestrel was deeply considered by means of Hansen solubility parameter concept. The obtained equilibrium solubility was computationally expressed by modified Jouyban–Acree–van’t Hoff model, mixture response surface (MRS) model, modified Wilson model and Jouyban–Acree model with the relative average deviations of no higher than 7.12%. The relative prominence of solvent–solvent and solute–solvent molecule interactions on etonogestrel solubility variation specified the dipolarity-polarizability and solubility parameter of solution descriptors that was studied in terms of the linear solvation energy relationships. The extended Hildebrand solubility approach was used to inspect the solubility data at 298.15 K acquiring the correlation coefficient of >0.9999. The quantitative investigation on preferential solvation of etonogestrel by solvent species in different solutions was made by the inverse Kirkwood–Buff integrals technique in terms of numerous solution properties. Positive preferential solvation parameters for cosolvents of isopropanol, DMF, ethanol and n-propanol in aqueous solutions with cosolvent-rich and intermediate scopes suggested the preferential solvation of etonogestrel by the cosolvents (isopropanol/DMF/ethanol/n-propanol). It was assumed that etonogestrel acted as a Lewis acid in these composition ranges with the isopropanol/DMF/ethanol/n-propanol molecules. Thermodynamic analysis of dissolution properties and enthalpy–entropy compensation demonstrated an entropy-driven mechanism and endothermic process for etonogestrel dissolved in different blended solvents.