Interlaboratory study of log P determination by shake-flask and potentiometric methods

Area of Science:

• Analytical Chemistry
• Medicinal Chemistry
• Physical Chemistry

Background:

• Accurate determination of physicochemical properties like pKa and log P is crucial for drug discovery and development.
• Traditional methods for log P determination can be time-consuming and resource-intensive.

Purpose of the Study:

• To evaluate the accuracy and reproducibility of potentiometric determination of pKa and log P.
• To compare potentiometric log P values with those obtained using the shake-flask method.
• To highlight the advantages of the potentiometric approach for characterizing drug-like molecules.

Main Methods:

• Potentiometric titration was used to determine pKa and log P values for 23 diverse compounds.
• Log P was also measured using the shake-flask method for comparative analysis.
• Interlaboratory reproducibility of the potentiometric pH-metric log P technique was assessed.

Main Results:

• Potentiometric measurements demonstrated excellent interlaboratory agreement for both pKa (average delta = +/-0.02) and log P (average delta = +/-0.07).
• Log P values determined by potentiometry and the shake-flask method showed very good concordance (r = 0.9987).
• The study covered a wide log P range (-1.84 to 5.80), demonstrating the method's broad applicability.

Conclusions:

• Potentiometry is a reliable and reproducible method for determining pKa and log P values.
• The pH-metric log P technique offers a valuable, accurate alternative to the shake-flask method.
• This method facilitates efficient characterization of compounds in pharmaceutical research.