Journal of Chromatography A, 1217 (2010) 3026–3037 Contents lists available at ScienceDirect Journal of Chromatography A journal homepage: www.elsevier.com/locate/chroma Determination of the hydrophobicity of organic compounds measured as log P o/w through a new chromatographic method Juan M. Pallicer a , Sandra Pous-Torres b , Joaquim Sales c , Martí Rosés a , Clara Ràfols a , Elisabeth Bosch a,∗ a Departament de Química Analítica and Institut de Biomedicina (IBUB), Universitat de Barcelona, Martí i Franquès 1-11, E-08028 Barcelona, Spain b Departament de Química Analítica, Universitat de València, Dr. Moliner 50, E-46100 Burjassot, València, Spain c Departament de Química Inorgànica, Universitat de Barcelona, Martí i Franquès 1-11, E-08028 Barcelona, Spain article info Article history: Received 18 December 2009 Received in revised form 16 February 2010 Accepted 22 February 2010 Available online 1 March 2010 Keywords: Hydrophobicity log P o/w HPLC Polarity model QSPR model abstract A new chromatographic method to determine the octanol–water partition coefficient (log P o/w ) of organic substances is proposed in this paper. This method is based on a previously reported model that relates the retention factor in reversed-phase liquid chromatography with solute (p), mobile phase (P N m ) and stationary phase (P N s ) polarity parameters: logk = (logk) 0 + p(P N m - P N s ). P N m values are calculated through expressions that depend only on the organic solvent fraction in the mobile phase. (log k) 0 and P N s parame- ters are characteristic of the chromatographic system and are determined from the retention of a selected set of 12 compounds. Then, the p value of a solute determined in a properly characterized system is easily derived from the retention factor data. Solute p values are slightly dependent on the chromatographic system but they are linearly related to those obtained in the reference system (Spherisorb ODS-2 column and acetonitrile as organic modifier). Therefore, they can be easily transferred from any experimental system to the reference one. A Quantitative Structure–Property Relationship study reveals that the p parameter in the reference chromatographic system depends, mainly, on the hydrophobicity of the com- pound, expressed as the n-octanol/water partition coefficient (log P o/w ), and five additional structural descriptors which can be easily calculated through the CODESSA program from the chemical structure of the solute. In this work the p descriptors of a wide set of structurally different organic compounds have been determined in several chromatographic systems and transferred to the reference one from these and the CODESSA structural parameters. The log P o/w values have been determined. The obtained values agree with those determined from classical experimental techniques and validate the new method as a useful tool to determine the hydrophobicity of a wide variety of compounds in a broad log P o/w range. © 2010 Elsevier B.V. All rights reserved. 1. Introduction It is widely recognized that the pioneer work published by Over- tone and Meyer at the end of the XIX century opened the door to the modern QSAR studies. Later, after the contribution of Han- sch and Fujita [1], many researchers have established relationships between octanol–water partition coefficient (log P o/w ), the most common index of lipophilicity, and biological activity of organic compounds or pharmacokinetic behaviour of drugs. As log P o/w plays this important role in ADMET properties of drugs (absorption, distribution, metabolism, excretion and toxicity), its measurement is essential in the first steps of drug discovery. The classical procedure to determine the log P o/w is the shak- ing flask method [2], which involves the control of a high number of experimental details if accuracy is required, and it is a highly ∗ Corresponding author. Tel.: +34 93 402 12 84; fax: +34 93 402 12 33. E-mail address: e.bosch@ub.edu (E. Bosch). time-consuming method. Potentiometric methods offer accurate results but are only suitable for acidic or basic compounds [3,4]. There are also several software packages (e.g., ClogP, AlogPs, ACD- Labs) to calculate log P o/w values but the results frequently show a lack of consistency among them because different log P o/w val- ues are obtained from different softwares, which apply different algorithms. Nowadays, reversed-phase high-performance liquid chromatography (RP-HPLC) is considered one of the best tech- niques for estimating octanol–water partition, due to its high throughput, insensitivity to impurities or degradation products, broader dynamic range, on-line detection, and reduced sample size. Lipophilicity indices in HPLC are usually derived from the loga- rithm of retention factor, log k, expressed as: logk = log  t r - t 0 t 0  (1) where t r and t o are the retention times of solute and void vol- ume marker, respectively. Isocratic log k values may be a relative scale of lipophilicity, but most researchers [5–13] prefer work- 0021-9673/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.chroma.2010.02.051