Lipophilicity and pKa estimates from gradient high-performance liquid chromatography

Area of Science:

• Analytical Chemistry
• Chromatography
• Physical Chemistry

Background:

• Estimating drug lipophilicity and acidity is crucial for drug discovery and development.
• Traditional methods for determining these parameters can be time-consuming and require significant sample amounts.
• The linear-solvent strength (LSS) model offers a potential framework for more efficient analysis.

Purpose of the Study:

• To apply the linear-solvent strength (LSS) model of gradient elution for estimating lipophilicity (log kw) and acidity (pKa) of drugs and model chemicals.
• To validate the accuracy of the LSS model-derived parameters against established methods.
• To assess the utility of this approach for high-throughput screening.

Main Methods:

• Utilized a 2-3 gradient run approach based on the LSS model.
• Employed a wide-range organic modifier gradient with suppressed analyte ionization in initial runs.
• Incorporated a pH-gradient in subsequent runs to determine apparent pKa values.
• Determined log kw by estimating the organic modifier content (%B) for non-ionized analytes.

Main Results:

• Apparent pKa and log kw values were determined for individual analytes within 2-3 gradient runs.
• Log kw values obtained via the LSS model showed good correlation with standard extrapolation methods.
• Log kw correlated well with lipophilicity parameter log P for test analytes and satisfactorily for diverse drug series.
• pKa values correlated with literature data for aniline derivatives but showed moderate correlation for general drug series.

Conclusions:

• The LSS model provides an efficient method for determining drug lipophilicity and acidity.
• This approach is suitable for rapid screening of lipophilicity in complex mixtures, such as those from combinatorial chemistry.
• The method demonstrates potential for accelerating early-stage drug discovery processes.