A novel computational strategy for the pKa estimation of drugs by non‐linear regression of multiwavelength spectrophotometric pH‐titration data exhibiting small spectral changes

A new computational procedure for the protonation model building of a multiwavelength and multivariate spectra treatment is proposed for the special case of small changes in spectra. The absorbance change Di for the ith spectrum divided with the instrumental standard deviation sinst(A) represents the signal-to-error ratio SERof the spectra studied. The determination of the number of chemical components in a mixture is thefirstimportant step for further quantitative analysis in all forms of spectral data treatment. Most index-based methods of the factor analysis can always predict the correct number of components, and even the presence of a minor one, when the SER is higher than 10. The Wernimont-Kankare procedure in the program INDICES performs reliable determinations of the instrumental standard deviation of the spectrophotometer used sinst(A), correctly predicts the number of light- absorbing components present, and also solves ill-defined problems with severe collinearity in spectra or very small changes in spectra. The mixed dissociation constants of three drugs, haemanthamine, lisuride, and losartan, including diprotic molecules at ionic strengths of I ¼0.5 and 0.01 and at 258C were determined using two different multi- wavelength and multivariate treatments of the spectral data, SPECFIT32 and SQUAD(84) non-linear regression analyses and INDICES factor analysis, even in the case of small absorbance changes in spectra. The dissociation constant pKa was estimated by non-linear regression of {pKa, I} data at 258C: for haemanthamine pKa ¼7.28(1) at I ¼0.50, for lisuride pKa ¼7.86(1) and for losartan pKa,1 ¼3.60(1), pKa,2 ¼4.73(1) at I ¼0.01. Goodness-of-fit tests for the various regression diagnostics enabled the reliability of the parameter estimates found to be proven. PALLAS and MARVIN predict pKa being based on the structural formulae of the drug compounds in agreement with the experimental value. Copyright # 2007 John Wiley & Sons, Ltd.

[1]  H. Gampp,et al.  Calculation of equilibrium constants from multiwavelength spectroscopic data-I Mathematical considerations. , 1985, Talanta.

[2]  D. Leggett,et al.  General computer program for the computation of stability constants from absorbance data , 1975 .

[3]  H. Gampp,et al.  Calculation of equilibrium constants from multiwavelength spectroscopic data-IV Model-free least-squares refinement by use of evolving factor analysis. , 1986, Talanta.

[4]  M. Meloun,et al.  Thermodynamic dissociation constants of codeine, ethylmorphine and homatropine by regression analysis of potentiometric titration data , 2000 .

[5]  Yang Li,et al.  Determination of the number of components in mixtures using a new approach incorporating chemical information , 1999 .

[6]  Milan Meloun,et al.  Thermodynamic dissociation constants of silychristin, silybin, silydianin and mycophenolate by the regression analysis of spectrophotometric data , 2003 .

[7]  A. Parczewski.  Chemometrics for Analytical Chemistry, Vol. 2: PC-aided Regression and Related Methods: by M. Meloun, J. Militky and M. Forina Prentice Hall, 1994, 418 pp., US$ 128.00, ISBN 0-13-132788-7 , 1995 .

[8]  T. Syrový,et al.  Tutorial on a chemical model building by least-squares non-linear regression of multiwavelength spectrophotometric pH-titration data. , 2006, Analytica chimica acta.

[9]  T. Syrový,et al.  The thermodynamic dissociation constants of ambroxol, antazoline, naphazoline, oxymetazoline and ranitidine by the regression analysis of spectrophotometric data. , 2004, Talanta.

[10]  Kin Yip Tam,et al.  Multi-wavelength spectrophotometric determination of acid dissociation constants: a validation study , 2001 .

[11]  D. J. Leggett,et al.  Numerical analysis of multicomponent spectra , 1977 .

[12]  T. Syrový,et al.  The thermodynamic dissociation constants of haemanthamine, lisuride, metergoline and nicergoline by the regression analysis of spectrophotometric data , 2005 .

[13]  Computer estimation of dissociation constants. Part V. Regression analysis of extended Debye-Hueckel law , 1992 .

[14]  Smoothed window factor analysis , 1999 .

[15]  Milan Meloun,et al.  Critical comparison of methods predicting the number of components in spectroscopic data , 2000 .

[16]  H. Gampp,et al.  Calculation of equilibrium constants from multiwavelength spectroscopic data--II: SPECFIT: two user-friendly programs in basic and standard FORTRAN 77. , 1985, Talanta.

[17]  J. Kankare.  Computation of equilibrium constants for multicomponent systems from spectrophotometric data , 1970 .

[18]  M. Meloun,et al.  Computation of Solution Equilibria , 1988 .

[19]  P. Gans,et al.  Investigation of equilibria in solution. Determination of equilibrium constants with the HYPERQUAD suite of programs. , 1996, Talanta.

[20]  M. Meloun,et al.  Multiparametric curve fitting--X: a structural classification of programs for analysing multicomponent spectra and their use in equilibrium-model determination. , 1986, Talanta.

[21]  T. Syrový,et al.  Determination of the number of light-absorbing species in the protonation equilibra of selected drugs , 2003 .

[22]  T. Syrový,et al.  The thermodynamic dissociation constants of losartan, paracetamol, phenylephrine and quinine by the regression analysis of spectrophotometric data , 2005 .

[23]  David J. Leggett,et al.  Computational methods for the determination of formation constants , 1985 .

[24]  M. Forina,et al.  PC-aided regression and related methods , 1994 .

[25]  K. Kadish,et al.  A computational approach to the spectrophotometric determination of stability constants-II Application to metalloporphyrin-axial ligand interactions in non-aqueous solvents. , 1983, Talanta: The International Journal of Pure and Applied Analytical Chemistry.

[26]  V. Meisalo,et al.  Equilibrium Constants and Model Testing from Spectrophotometric Data Using LETAGROP. , 1968 .

[27]  M. Meloun,et al.  Strategies for Solution Equilibria Studies with Specific Reference to Spectrophotometry , 1985 .