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Quantitative structure-(chromatographic) retention relationship models for dissociating compounds

Published on Aug 1, 2016in Journal of Pharmaceutical and Biomedical Analysis2.983
· DOI :10.1016/j.jpba.2016.02.050
Łukasz Kubik9
Estimated H-index: 9
(Gdańsk Medical University),
Paweł Wiczling18
Estimated H-index: 18
(Gdańsk Medical University)
Abstract
Abstract The aim of this work was to develop mathematical models relating the hydrophobicity and dissociation constant of an analyte with its structure, which would be useful in predicting analyte retention times in reversed-phase liquid chromatography. For that purpose a large and diverse group of 115 drugs was used to build three QSRR models combining retention-related parameters (log k w —chromatographic measure of hydrophobicity, S—slope factor from Snyder-Soczewinski equation, and p K a ) with structural descriptors calculated by means of molecular modeling for both dissociated and nondissociated forms of analytes. Lasso, Stepwise and PLS regressions were used to build statistical models. Moreover a simple QSRR equations based on lipophilicity and dissociation constant parameters calculated in the ACD/Labs software were proposed and compared with quantum chemistry-based QSRR equations. The obtained relationships were further used to predict chromatographic retention times. The predictive performances of the obtained models were assessed using 10-fold cross-validation and external validation. The QSRR equations developed were simple and were characterized by satisfactory predictive performance. Application of quantum chemistry-based and ACD-based descriptors leads to similar accuracy of retention times’ prediction.
  • References (16)
  • Citations (9)
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Fast and reliable methods for the determination of hydrophobicity and acidity are desired in pre-clinical drug development phases to eliminate compounds with poor pharmacokinetic properties. Reversed-phase high-performance liquid chromatography (RP HPLC) coupled with time-of-flight mass spectrometry (RP HPLC–ESI-TOF–MS) is a convenient technique for that purpose. In this work we determined the chromatographic measure of hydrophobicity (log kw) and dissociation constant (pKa) simultaneously for a...
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The aim of this work was to develop a nonlinear mixed-effect chromatographic model able to describe the retention times of weak acids and bases in all possible combinations of organic modifier content and mobile-phase pH. Further, we aimed to identify the influence of basic covariates, like lipophilicity (log P), dissociation constant (pKa), and polar surface area (PSA), on the intercompound variability of chromatographic parameters. Lastly, we aimed to propose the optimal limited experimental d...
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