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A comprehensive method for determining hydrophobicity constants by reversed-phase high-performance liquid
D J Minick1, J H Frenz, M A Patrick
1Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709.
Journal of Medicinal Chemistry
|October 1, 1988
Summary
A new reversed-phase liquid chromatography (RPLC) method determines hydrophobicity constants for organic molecules. This method, using derived values (log k'w), offers improved accuracy and automation over traditional techniques.
Area of Science:
- Analytical Chemistry
- Chromatography
- Physical Chemistry
Background:
- Hydrophobicity constants are crucial for understanding drug behavior and molecular interactions.
- Traditional methods like octanol-water partition coefficients (log Po/w) face challenges such as peak inversion and are not easily automated.
- Reversed-phase liquid chromatography (RPLC) offers potential for hydrophobicity determination but requires refined methodologies.
Purpose of the Study:
- To develop a novel method for determining hydrophobicity constants of small organic molecules using RPLC.
- To establish a new hydrophobicity scale based on derived capacity ratio values (log k'w).
- To address limitations of existing RPLC methods for hydrophobicity assessment, including peak inversion and differential hydrogen bonding effects.
Main Methods:
- Utilized capacity ratios measured across various methanol compositions in RPLC.
- Introduced trace amounts of n-decylamine and 1-octanol to the eluent to minimize hydrogen bonding effects.
- Employed an octyl-modified silica gel stationary phase.
- Developed a new hydrophobicity scale using derived log k'w values.
Main Results:
- The developed RPLC method yields hydrophobicity constants (log k'w) that are largely column-independent for similar stationary phases.
- The method effectively minimizes differential hydrogen bond effects, improving correlation accuracy.
- The derived log k'w values correlate with bovine serum albumin binding constants (log 1/C) as effectively as log Po/w.
- The chromatographic system is automatable, enabling higher sample throughput.
Conclusions:
- The novel RPLC method provides a robust and automatable approach for determining hydrophobicity constants.
- The new hydrophobicity scale (log k'w) overcomes limitations of traditional methods and isocratic RPLC.
- This method offers a valuable alternative for assessing molecular hydrophobicity and predicting protein binding.