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 HSC10(CH2CH2O)6C18 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 (R2 = 0.933) was established between log(−dF/Mwt) 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 pKa could be determined by profiling log D changes during pH titration. The lipophilicity/pH profile of a weakly basic drug (quinine; pKa = 7.95) was sigmoidal with respect to −dF/Mw values, with a profile inverse to that of a weakly acidic drug (naproxen; pKa = 4.15).