Historical

The classical studies by Overton and Meyer, and later Fujita and Hansch, demonstrated that partition coefficients (log P values) can be correlated with many biological phenomena. It is beyond doubts that log P are among the most important descriptors for transport processes of a biologically active compound in the body.

However, log P measurements are time-consuming and are limited to a certain, range, e.g., — 3<log Poa<3. Beyond these limits, the log P values assessed by the shake flask method become unreliable. Alternatives, particularly chromatographic methods, have therefore been evaluated and used successfully to assess lipophilicity of organic compounds. These include thin-layer chromatography (TLC, see Chapter 8), centrifugal partition chromatography (CPC, see Chapter 6), and reversed-phase highperformance liquid chromatography (RP-HPLC or RPLC). The fitst applications of lipophilicity measurements by HPLC go back to the 1970s [1-4]. A review of this early work can be found in reference [5]; more recent work is reviewed in reference [6].

It is not the intention of the authors of the present chapter to be comprehensive, since the literature on this topic literally exploded over the last 20 years. The most important subjects, critical issues, and selected recent findings will be presented here. Particularly of interest are the various packing materials, since identification of lipophilicity scales correlated with biologically important transport and distribution processes, such as gastrointestinal absorption, skin penetration, blood-brain-barrier uptake, plasma protein binding is of great interest to drug discovery. The interest of certain solid phases is their close resemblance to octanol/water partitioning, which is still considered as the standard system. Particularly some new materials, such as immobilized artificial membranes (IAM) may have a good future, since they mimic transport through biological barriers.

Besides the well-known techniques based on RP-HPLC or RPLC (or RPC), other related chromatographic methods useful for lipophilicity measurements will be briefly mentioned, such as ion pair chromatography (IPC), micelle liquid chromatography (MLC) and hydrophobic interaction chromatography (HIC).

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