The co-solvency and thermodynamic properties calculation of flunarizine hydrochloride in mixtures of (acetonitrile/ethyl acetate + isopropanol)

• Improve the solubility of flunarizine hydrochloride by co-solvent. • The result of solubility data was correlated by Jouyban-Acree model and CNIBS/R-K model. • The co-solvency phenomenon was discussed. • Some of apparent thermodynamic properties were calculated. The solubility of flunarizine hydrochloride was improved by co-solvent in this work. In (acetonitrile + isopropanol) and (ethyl acetate + isopropanol) binary mixtures, it was measured at the temperature range from T = (273.15 To 313.15) K by the isothermal equilibrium method under 101.3 kPa. The solubility values in two mixtures increased firstly and then decreased with the increasing mass fraction of acetonitrile or ethyl acetate, and reached the maximum when the mass fraction of acetonitrile ( w ) = 0.60, and ethyl acetate ( w ) = 0.40 at all investigated temperatures. In pure solvents, the largest solubility is obtained in isopropanol, followed by acetonitrile and ethyl acetate. In mixture of (acetonitrile + isopropanol), the maximum and minimum values at 298.15 K are 5.98 × 10 −3 and 2.91 × 10 −3 , respectively, and 5.91 × 10 −3 and 2.24 × 10 −3 in mixture of (ethyl acetate + isopropanol). The Jouyban-Acree model and CNIBS/R-K model were used to evaluate the results. Moreover, the relative contributions of solvent–solvent and solute–solvent interactions on the drug solubility variation were studied via the analysis of linear solvation energy relationships. The maximum value of relative average deviation ( RAD ) of Jouyban-Acree model was 4.20% in mixture of (acetonitrile + isopropanol), and for CNIBS/R-K model, it was 5.34% at 298.15 K in mixture of (acetonitrile + isopropanol). All values of apparent dissolution standard enthalpy ( Δ H sol o ), apparent molar standard Gibbs energy ( Δ G sol o ) and apparent dissolution standard entropy ( Δ S sol o ) are positive, which indicates the dissolution process is endothermic and entropy-increasing. The results of the relative contributions by enthalpy ( ζ H ) and by entropy ( ζ TS ) toward to Gibbs energy of the solution process show that the enthalpy is the main contributor to standard free energy of solution process.