In this study, the ionization constants (pK(a)) of sulfonylurea group antidiabetic drugs (glibenclamide, gliclazide, glimepiride, and glipizide) were calculated, providing significant information about the physicochemical properties of the drugs. Potentiometric titration and reverse-phase liquid chromatography were used to determine the ionization constants in tetrahydrofuran (THF)-water media. The PKPOT and NLREG computer programs were used to evaluate the results. In addition, the aqueous pK(a) values of the compounds were calculated using the Yasuda-Shedlovsky equation and mole fraction-pK(a) extrapolation methods. When the potentiometric titration method was used, the aqueous pK(a) values of glibenclamide, gliclazide, glimepiride, and glipizide were calculated to be 6.002, 6.085, 6.106, and 6.016, respectively, using the Yasuda-Shedlovsky equation, while the mole fraction-pK(a) extrapolation method gave 6.013, 6.096, 6.117, and 6.027, respectively. On the other hand, when the RPLC method was used, pK(a) values of 5.489, 5.732, 5.733, and 5.601, respectively, were obtained with the Yasuda-Shedlovsky equation and mole fraction-pK(a) extrapolation gave 5.499, 5.742, 5.743, and 5.611, respectively. The ionization constants obtained with these methods provide valuable information for researchers studying these active pharmaceutical compounds.