title: Measurement of drug lipophilicity and pKa using acoustics.
abstract: Lipophilicity of chemicals and drug candidates is normally described in terms of octanol/water partitioning and log P. We investigated an alternate approach to lipophilicity determination using a mimic of an alkyl alcohol with compound partitioning quantified using acoustic sensing. A self-assembled monolayer composed of HSC(10)(CH(2)CH(2)O)(6)C(18) was formed on planar gold electrodes of a piezoelectric acoustic sensor. The system was challenged with compounds covering a 4-log range of log D values. As compounds partitioned in the interfacial layer, changes in sensor resonant frequency were found to correlate with compound partition coefficients (log P) and with distribution coefficients (log D). Linear concordance (R(2) = 0.933) was established between log(-dF/M(w)t) and log P and with log D in both water and biological buffers at variant pH (pH 5.2 to 7.8). In turn, drug pK(a) could be determined by profiling log D changes during pH titration. The lipophilicity/pH profile of a weakly basic drug (quinine; pK(a) = 7.95) was sigmoidal with respect to -dF/M(w) values, with a profile inverse to that of a weakly acidic drug (naproxen; pK(a) = 4.15).
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cooper
mesh_terms: D000162:Acoustics / Q000295:instrumentation*; D055664:Electrochemical Techniques / Q000295:instrumentation*; D004566:Electrodes; D004867:Equipment Design; D005026:Ethylene Glycols / Q000737:chemistry; D006046:Gold / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D008055:Lipids / Q000737:chemistry*; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D013229:Stearic Acids / Q000737:chemistry; D013499:Surface Properties
chemical_list: D005026:Ethylene Glycols; D008055:Lipids; D004364:Pharmaceutical Preparations; D013229:Stearic Acids; C077067:hexaethylene glycol; D006046:Gold