Theoretical calculation of pKa values of the Nortryptiline and Amitryptiline drugs in aqueous and non-aqueous solvents

In this work, calculations of pKa values have been performed on the Nortryptiline and Amitryptiline drugs in aqueous and non-aqueous solvents. Gas-phase energies were calculated by different DFT methods such as BLYP, B3LYP, BP86, B3P86, BPW91, B3PW91, OLYP, O3LYP, BB95, B1B95, M05, M05-2X, M06 and M06-2X with 6-31 + G(d) basis set. Free energy of solvation were calculated by applying the conductor-like polarizable continuum model (CPCM), SM50R and SM8 solvation models at the HF/6-31 + G(d) level of theory. The CPCM calculations were employed with the UA0, UAHF, UAKS, UFF, Bondi and Pauling atomic radii. The results indicated the calculated pKa values by Pauling radii were better than other cavity models. In addition, the calculated pKa values using hybrid forms of the generalized gradient approximation and meta-generalized gradient approximation functionals were better than their corresponding pure forms. Also, the good agreement between the experimental and the calculated pKa values of the Nortryptiline and Amitryptiline drugs in water and methanol solvents was observed. Moreover, the pKa values of drugs in ethanol solvent were predicted.