Thermodynamic dissociation constants of codeine, ethylmorphine and homatropine by regression analysis of potentiometric titration data Original Research Article

Concentration and mixed dissociation constant(s) of three drug acids HJL, codeine, ethylmorphine and homatropine, at various ionic strengths I in the range of 0.03–0.81 have been determined with the use of regression analysis of potentiometric titration data when common parameters (pKa,j, j=1, …, J), and group parameters (E0′, L0, HT) are simultaneously refined. Reliability of the dissociation constant(s) should be proven because three group parameters (E0′, L0, HT) are ill-conditioned in the regression model and have influence on systematic error in the estimated pKa. Internal calibration of the glass electrode cell in the concentration (stoichiometric) scale [H+] performed during titration was used. The thermodynamic dissociation constant pKaT, an ill-conditioned ion-size parameter å [10−8 m] and the salting-out coefficient C were estimated by nonlinear regression of {pKa, I} data. Goodness-of-fit tests provide various regression diagnostics enabling the reliability of parameters at 25°C to be proven. For codeine pKaT=8.31±0.01, å=4±1 [10−8 m], C=0.45±0.04; for ethylmorphine pKaT=8.17±0.01, å=8±2 [10−8 m], C=0.54±0.03; and for homatropine pKaT=9.90±0.01, å=6±2 [10−8 m], C=0.51±0.03.