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An increased throughput method for the determination of partition coefficients.
L Hitzel1, A P Watt, K L Locker
1Merck Sharp and Dohme, Neuroscience Research Centre, Essex, United Kingdom.
Pharmaceutical Research
|February 24, 2001
Summary
This study introduces an automated shake-flask method for faster determination of partition coefficients (log D values). The high-throughput technique enables rapid assessment of large compound arrays, improving drug discovery efficiency.
Area of Science:
- Analytical Chemistry
- Physical Chemistry
- Pharmacokinetics
Background:
- The traditional shake-flask method for determining partition coefficients (log D) is time-consuming and labor-intensive.
- Accurate log D values are crucial for predicting drug absorption, distribution, metabolism, and excretion (ADME) properties.
- High-throughput screening methods are essential for modern drug discovery to efficiently evaluate large compound libraries.
Purpose of the Study:
- To develop and validate an automated, high-throughput shake-flask method for direct determination of partition coefficients (log D).
- To significantly increase the throughput of log D measurements compared to traditional methods.
- To provide a robust platform for rapid assessment of solute partitioning between octan-1-ol and aqueous buffers.
Main Methods:
- Adaptation of the shake-flask method to 96-well plate technology for parallel processing.
- Utilized a robotic liquid handler for automated sample preparation and pipetting.
- Employed a custom-programmed autosampler for direct sampling of organic and aqueous phases, eliminating manual separation.
- Analyzed samples using generic, fast gradient reverse-phase high-performance liquid chromatography (RP-HPLC) to minimize method development time.
Main Results:
- Successfully validated the automated method for a diverse range of compounds.
- Demonstrated accurate log D value determination across a wide range, from -2 to 4.
- Achieved significantly increased throughput for partition coefficient measurements.
Conclusions:
- The automated shake-flask method offers a rapid and efficient means to determine log D values for extensive compound collections.
- This direct measurement technique streamlines early-stage drug discovery by enabling faster compound profiling.
- The method's advantages include reduced analysis time and elimination of manual separation steps, though its limitations should be considered.