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 degrees C have been determined with the use of r egression analysis of potentiometric titration data when common parameter, pK(a), and group parameters E'(0), L-0, and H-T are simultaneously refined. Internal calibration of the glass electrode cell in the concentration scal e [H+] performed during titration was used. The estimate of ill-conditioned group parameters has a great influence on a systematic error in estimated pK(a) and therefore it makes the computational strategy important. As more group parameters are refined and a better fit achieved, a more reliable est imate of dissociation constants results. The thermodynamic dissociation con stant, pK(a)(T), an ill-conditioned ion-size parameter, (a) over circle, an d the salting-out coefficient, C, were estimated by non-linear regression o f {pK(a), I} data and an extended Debye-Huckel equation. The goodness-of-fi t test based on regression diagnostics is a measure of the reliability of p arameters, and proves that reliable estimates for isocaine pK(a)(T) = 8.96( 1), (a) over circle = 8(3) Angstrom and C = 0.50(3) at 25 degrees C, for ph ysostigmine pK(a)(T) = 8.07(3), (a) over circle = 19(26) Angstrom and C = 0 .64(3) at 25 degrees C, and for pilocarpine pK(a)(T =) 7.00(1), (a) over ci rcle = 7(1) Angstrom and C = 0.53(2) at 25 degrees C were found. (C) 2000 E lsevier Science B.V. Ail rights reserved.