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

Abstract

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). Moreover, the unionized form of solutes is usually taken as the reference state for the measurement of lipophilicity. This can be problematic for the RP-HPLC determination of lipophilicity of acidic compounds due to the limited pH operating 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 and 5.70; consequently, the lipophilicities of the unionized forms must be measured at pH below 2. Accordingly, their capacity factors (log k_w) were determined on a column packed with a hydrophilic polymethacrylate gel having octadecyl groups. This RP-column allows separations at low pH values of the mobile phase. In practice, the values of log k_w are obtained by a series of isocratic measurements at various compositions of binary acetonitrile-water eluents and extrapolation of the relationship between log k and volume fraction of organic solvent, φ, to 100% water. The 1-octanol-water partition 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 behaviour of these drugs for the two partitioning processes.

This excellent correlation prompted us to validate this polymer-based column, to be useful for the determination of other acidic drug lipophilicity.

ACKNOWLEDGMENT

The authors wish to thank Mrs Evelyne Déridet for her technical assistance during this study.