Application

log P Measurements

The octanol-water partition coefficient (log P value) of a drug substance is an indicator of compound lipophilicity and solubility. The log P value is a useful parameter in Drug Discovery and Development and is used to predict transport properties across cell membranes, establish quantitative structure-activity relationships (QSARs), and as an indicator of protein binding characteristics.

Classical log P measurement techniques using "shake-flask" or potentiometry are time consuming and require relatively large amounts of pure compound. Potentiometric methods also require an ionizable group to measure log P. Methods based on liquid chromatography are generally serial in nature and relatively low throughput. The pKa PRO™ system enables parallel, accurate, separation-based log P measurements that are insensitive to impurities and consume minimal amounts of sample.

Key Benefits:

• The pKa PRO™ system, equipped with the log P application package, provides automated measurements of neutral and basic compounds over the log P range of -0.5 to 5.0 with a throughput of up to 46 samples/h. Basic compounds should have a pKa value less than 10 to minimize charge effects.
• The use of microemulsion electrokinetic chromatography (MEEKC) provides a validated method with good correlation to the traditional "shake flask" technique.
• The method requires only microgram quantities of compound and is separation-based. As a result, impurities and degradants can be detected and isolated from the target compound.
• Intimate knowledge of sample concentrations is not required. Only migration times are utilized for the measurement.
• Pre-made buffers, sample diluents and application-specific software provide a "turn-key" package for sample analysis.
• The pKa PRO™ system is flexible and can be readily configured for performing pKa measurements, chiral separations and analytical scale small molecule separations.

The graphics above show a representative separation of a seven peak standard log P mixture and the corresponding system calibration curve. The capacity factor (log k′) for each standard is plotted from the difference in migration times between the standard, DMSO marker and microemulsion (ME) marker. The log k′ values are plotted as a function of literature log P values (R2 > 0.98) to calibrate the system. Unknown sample log P values are then interpolated from measured log k′ values using the calibration curve.

 

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