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Recent Pprogress in the pKa Estimation of Druglike Molecules by the Nonlinear Regression of Multiwavelength Spectrophotometric pH-titration Data
Authors: Meloun Milan | Syrový Tomáš | Vrána Aleš
Year: 2007
Type of publication: článek v odborném periodiku
Name of source: Journal of Pharmaceutical Science
Publisher name: Wiley-Blackwell
Page from-to: 11-12
Titles:
Language Name Abstract Keywords
cze Poslední vývoj metod odhadu pK léčiv nelineární regresí pH titračních spekter Jsou uvedeny nově zaváděné diagnostické počítačové pomůcky k odhadu pK léčiv při nelineární regresi pH spekter a demonstrovány na protonačních rovnováhách vícesytné kyseliny léčiva silybinu. I když většina metod faktorové analýzy k určení hodnosti absorbanční matice čili počtu světlo-absorbujících částic potřebuje hodnotu SER (signal k šumu přístroje) větší než 10, Wernimont-Kankareho metoda v programu INDICES bezpečně i zde určila počet částic rovnovážného systému. Disociační konstanty byly odhadnuty nelineární regresí spekter programem SQUAD a SPECFIT32. Věrohodnost odhadů disociačních konstant byla posuzována na základě testu těsnosti proložení vypočtených spekter experimentálními body, na základě dekonvoluce spekter a na základě faktorové analýzy. Nalezené hodnoty byly v dobré shodě s predikovanými hodnotami ze strukturního vzorce programy PALLAS a MARVIN. Spektrofotometrická titrace, disociační konstanta, protonace, silybin, SPECFIT, SQUAD, INDICES, PALLAS, MARVIN
eng Recent Pprogress in the pKa Estimation of Druglike Molecules by the Nonlinear Regression of Multiwavelength Spectrophotometric pH-titration Data Recent development in the computational diagnostic tools for the pKa estimation of druglike molecules carried out by the nonlinear regression of multiwavelength spectrophotometric pH-titration data are demonstrated on the protonation equilibria of silybin. Most indicesbased methods in the factor analysis of spectra predict the correct number of components even in the presence of a minor one or in cases of overlapping equilibria when the signal-to-error ratio SER is higher than 10. The Wernimont-Kankare procedure in the INDICES program performs a reliable determination of the instrumental standard deviation of the spectrophotometer used sinst(A) and correctly predicts the number of light-absorbing components present. It can also solve an ill-defined problem with severe colinearity in the data set, with very small changes in spectra and overlapping equilibria. The mixed dissociation constants of the drug silybin at ionic strength I = 0.03 and a temperature of 25oC were determined using two different programs, SPECFIT32 and SQUAD(84). A proposed experimental and computational strategy for the determination of the dissociation constants is presented. The dissociation constant pKa was estimated by nonlinear regression of the {pKa, I} data at 25oC with SQUAD (and SPECFIT), i.e. pKa1 = 6.898(0.022) and 6.897(0.002), pKa2 = 8.666(0.021) and 8.667(0.012), pKa3 = 9.611(0.010) and 9.611(0.004), pKa4 = 11.501(0.008) and 11.501(0.007). While great progress has been achieved in terms of the reliability of the protonation model estimation, among the most efficient diagnostics of the nonlinear regression of multiwavelength pH-spectra are the goodness-of-fit test, Cattel?s scree plot of the factor analysis, spectra deconvolution, the signal-to-error SER ratio analysis and other tools of efficient spectra analysis. Spectrophotometric titration, dissociation constant, protonation, silybin, SPECFIT, SQUAD, INDICES, PALLAS, MARVIN

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