a b s t r a c t In this work, calculations of pK a 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, 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 pK a values by Pauling radii were better than other cavity models. In addition, the calculated pK a values using hybrid forms of the general-ized 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 pK a values of the Nortryptiline and Amitryptiline drugs in water and methanol solvents was observed. Moreover, the pK a values of drugs in ethanol solvent were predicted. Ó 2013 Elsevier B.V. All rights reserved.