Thermodynamic dissociation constants of isocaine, physostigmine and pilocarpine by regression analysis of potentiometric data

Concentration and mixed dissociation constant(s) of three drug acids, HJL, isocaine, physostigmine and pilocarpine, at various ionic strengths, I, in the range 0.03–0.81 and 25°C have been determined with the use of regression analysis of potentiometric titration data when common parameter, pKa, and group parameters E′0, L0, and HT are simultaneously refined. Internal calibration of the glass electrode cell in the concentration scale [H+] performed during titration was used. The estimate of ill-conditioned group parameters has a great influence on a systematic error in estimated pKa and therefore it makes the computational strategy important. As more group parameters are refined and a better fit achieved, a more reliable estimate of dissociation constants results. The thermodynamic dissociation constant, pKaT, an ill-conditioned ion-size parameter, å, and the salting-out coefficient, C, were estimated by non-linear regression of {pKa, I} data and an extended Debye–Hückel equation. The goodness-of-fit test based on regression diagnostics is a measure of the reliability of parameters, and proves that reliable estimates for isocaine pKaT=8.96(1), å=8(3) Å and C=0.50(3) at 25°C, for physostigmine pKaT=8.07(3), å=19(26) Å and C=0.64(3) at 25°C, and for pilocarpine pKaT=7.00(1), å=7(1) Å and C=0.53(2) at 25°C were found.