In the study, the retention times (t(R)) values for meclizine (MCZ) and buclizine (BCZ) structurally related benzhydrylpiperazine were determined to modeling the dependence of retention on the acetonitrile concentration in the mobile phase. Reversed-phase liquid chromatography (RPLC) analysis of the MCZ and BCZ was realized with polar embedded amide (15x0.46 cm I.D, 5 mu m) column. The mobile phase pH range is selected from 5.0-9.0 to determine the structural changes due to protonation that result from a change in pH. The different retention time were attributed to their different hydrophobicities and ionization degree. The thermodynamic protonation constant ((S)(S)pK(a)) value for investigated compounds was calculated using the t(R) relationship to pH of the mobile phase and effect of the activity coefficients. Linear correlation between (S)(S)pK(a) values and macroscopic parameters (X-ACN, 1/epsilon) was also determined.