Study of the lipophilicity of arylpropionic non-steroidal anti-inflammatory drugs. A comparison between LC retention data on a polymer-based column and octanol-water partition coefficients

Molecular lipophilicity can be expressed by log P-ow or, more conveniently, by log k(w) i.e., determined by the traditional shake-flask technique, or by reversed-phase high performance liquid chromatography (RP-HPLC). Moreove r, the unionized form of solutes is usually taken as the reference state fo r the measurement of lipophilicity. This can be problematic for the RP-HPLC determination of lipophilicity of acidic compounds due to the limited pH o perating range of silica bonded phases. The measured dissociation constant values (pKa) of the twelve arylpropionic non steroidal antiinflammatory drugs (NSAIDs) are comprised between 3.80 a nd 5.70; consequently, the lipophilicities of the unionized forms must be m easured at pH below 2. Accordingly, their capacity factors (log k(w)) were determined on a column packed with a hydrophilic polymethacrylate gel havin g octadecyl groups. This RP-column allows separations at low pH values of t he mobile phase. In practice, the values of log k(w) are obtained by a seri es of isocratic measurements at various compositions of binary acetonitrile -water eluents and extrapolation of the relationship between log k and volu me fraction of organic solvent, phi, to 100% water. The 1-octanol-water par tition coefficients (log P-ow) of these NSAIDs were determined by the shake -flask technique using a conventional methodology. A significant linear relationship was obtained between log P-ow and log k(w ) with a slope close to unity, indicating similar intrinsic thermodynamic b ehaviour of these drugs for the two partitioning processes. This excellent correlation prompted us to validate this polymer-based colum n, to be useful for the determination of other acidic drug lipophilicity.