Alternative Lipophilicity Scales

Since 1-octanol has certain limitations (see Section 1.3) many alternative lipophilicity scales have been proposed (see Figure 1.8). A critical quartet of four solvent systems of octanol (amphiprotic), alkane (inert), chloroform (proton donor) and propy-... 

A CRO may also allow for the in-house introduction of specialized lipophilic scales by transferring routine measurements. While the octanol-water scale is widely applied, it may be advantageous to utilize alternative scales for specific QSAR models. Solvent systems such as alkane or chloroform and biomimetic stationary phases on HPLC columns have both been advocated. Seydel [65] recently reviewed the suitabihty of various systems to describe partitioning into membranes. Through several examples, he concludes that drug-membrane interaction as it relates to transport, distribution and efficacy cannot be well characterized by partition coefficients in bulk solvents alone, including octanol. However, octanol-water partition coefficients will persist in valuable databases and decades of QSAR studies. 

Other factors important to the choice of catalyst are its stability under the reaction conditions (see Section 1.1) and its removal from the organic phase at the end of the reaction. Ideally, the catalyst should be sufficiently hydrophilic to be washed from the product by water, but any catalyst having this property has, by implication, a lower lipophilicity and lower catalytic effect. Where the product is volatile, it can be separated from the catalyst and isolated by fractional distillation of the organic phase or, alternatively, the catalyst can be precipitated from the concentrated organic phase by the addition of a non-polar solvent, such as diethyl ether, and removed by filtration. On a small scale, the catalyst can be separated efficiently by direct chromatography of the organic phase from, for example, silica. This procedure is, however,... 

In addition or alternatively to these fields, hydrophobic fields, calculated e.g., by the program HINT, or GRID fields can be used. Arbitrary weights may be attributed to the different fields. An appropriate scaling of all variables has to be performed if additional properties, e.g., the lipophilicity parameter log P P = n-octanol/water partition coefficient), are included, to give a comparable weight to the individual fields and the single parameter(s). 

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