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

Concentration and mixed dissociation constant(s) of three drug acids HJL, c odeine, 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 (pK(a,j), j = 1,.. ., J), and group parameters (E-0, L-0, H-T) are simultaneously refined. Rel iability of the dissociation constant(s) should be proven because three gro up parameters (E-0', L-0, H-T) are ill-conditioned in the regression model and have influence on systematic error in the estimated pK(a),. Internal ca libration of the glass electrode cell in the concentration (stoichiometric) scale [H+] performed during titration was used. The thermodynamic dissocia tion constant pK(n)(T), an ill-conditioned ion-size parameter (a) over circ le [10(-8)m] and the salting-out coefficient C were estimated by nonlinear regression of {pK(a), I} data. Goodness-of-fit tests provide various regres sion diagnostics enabling the reliability of parameters at 25 degrees C to be proven. For codeine pK(a)(T) = 8.31 +/- 0.01, a = 4+/- 1 [10(-8)m], C = 0.45 +/- 0.04; for ethylmorphine pK(a)(T) = 8.17 +/- 0.01, (a) over circle = 8 +/- 2 [10(-8) m], C = 0.54 +/- 0.03; and for homatropine pK(a)(T) = 9.9 0 +/- 0.01, (a) over circle = 6 +/- 2 [10(-8) m], C = 0.51 +/- 0.03. (C) 20 00 Elsevier Science B.V. All rights reserved.