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<p>Determination of a compound’s log<i>P</i> and p<i>K</i><sub>a</sub> is advantageous in early stages of drug discovery. High pressure liquid chromatography (HPLC) is a viable, high throughput tool that is well-suited for such applications. The advantages stem from the minimal required analyte quantity and the ability to analyse samples of low purity and low water solubility. Determination of log<i>P</i> and p<i>K</i><sub>a</sub> via HPLC often utilises reversed phase mode, leveraging the fact that the analyte’s ionisation state affects its hydrophobicity and therefore retention. Estimation of both parameters can be performed under either isocratic or gradient elution, applying linear solvent strength theory. Hereby, we present a&#xa0;novel mobile phase blending method aimed to fully automatise the log<i>P</i> and <i>p</i>K<sub>a</sub> determination process. The method uses buffer blending by pumps to produce mobile phases in the range of pH = 2.5–8.6 within the liquid chromatography system. A positive correlation was observed between our determined log<i>k</i><sub>w</sub> values and the experimental log<i>P</i> found in literature, for a series of drug compounds. The p<i>K</i><sub>a</sub> estimation shows satisfying results in isocratic measurements and solely aqueous mobile phase. The method enables a linear pH gradient generation, likewise applicable for p<i>K</i><sub>a</sub> determination.</p> Graphical Abstract <p></p>

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Automatised liquid chromatography buffer blending method for logP and weak electrolyte pKa determination for early stages of drug discovery

  • 期刊论文

  • 发表日期：

    2026年8月5日

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  • Tímea Dérerová,
  • Květa Kalíková

摘要

Determination of a compound’s logP and pKa is advantageous in early stages of drug discovery. High pressure liquid chromatography (HPLC) is a viable, high throughput tool that is well-suited for such applications. The advantages stem from the minimal required analyte quantity and the ability to analyse samples of low purity and low water solubility. Determination of logP and pKa via HPLC often utilises reversed phase mode, leveraging the fact that the analyte’s ionisation state affects its hydrophobicity and therefore retention. Estimation of both parameters can be performed under either isocratic or gradient elution, applying linear solvent strength theory. Hereby, we present a novel mobile phase blending method aimed to fully automatise the logP and pKa determination process. The method uses buffer blending by pumps to produce mobile phases in the range of pH = 2.5–8.6 within the liquid chromatography system. A positive correlation was observed between our determined logkw values and the experimental logP found in literature, for a series of drug compounds. The pKa estimation shows satisfying results in isocratic measurements and solely aqueous mobile phase. The method enables a linear pH gradient generation, likewise applicable for pKa determination.

Graphical Abstract