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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-

Fig. 1.7 Iso-molecular weight curves showing the influence of molecular size on membrane permeability with increasing lipophilicity [32].

log Dat pH 7.4

Fig. 1.7 Iso-molecular weight curves showing the influence of molecular size on membrane permeability with increasing lipophilicity [32].

1.6 Computational Approaches to Lipophilicity |9

lene glycol dipelargonate (PGDP) has been advocated [33-34]. By measuring distribution in all four, a full coverage of partitioning properties should be obtained. Also non-aqueous systems such as heptane/acetonitrile [35] or heptane/glycol [36] may be of use. This latter system appears to offer a direct measure for hydrogen bonding. In order to increase throughput over the traditional shake-flask and related methods, various chromatographic techniques can be used [1]. Immobilized artificial membranes (IAM) in particular, have been given considerable attention [37, 38]. IAMs consist of phospholipids grafted onto a solid phase HPLC support intended to mimic a membrane. It appears that IAM retention times are highly correlated with shake flask log D octanol/water coefficients and thus do not really measure anything new. Along the same lines several groups have suggested that studying partitioning into liposomes may produce relevant information related to membrane uptake and absorption [38, 39].

Fig. 1.8 Experimental methods to measure lipophilicity (modified after reference [23 ]). log Poct, 1-octanol/water partition coefficient; log Pliposomes, partition coefficient between liposomes and buffer; log Phexane, 1-hexane/water partition coefficient; logPPGDP, propyleneglycol dipelargonate/water partition coefficient; log Pheptane/glycol, a non-aqueous partitioning system; SF, shake-flask; pH-metric, log P determination based on potentiometric titration in water and octanol/water; CPC, centrifugal partition chromatography; RP-HPLC, reversed-phase high performance liquid chromatography; TLC, thin-layer chromatography; ODS, octa-decylsilane; ABZ, end-capped silica RP-18 column; ODP, octade-cylpolyvinyl packing; IAM, immobilized artificial membrane; ILC, immobilized liposome chromatography; MEKC, micellar electrokinetic capillary chromatography.

Fig. 1.8 Experimental methods to measure lipophilicity (modified after reference [23 ]). log Poct, 1-octanol/water partition coefficient; log Pliposomes, partition coefficient between liposomes and buffer; log Phexane, 1-hexane/water partition coefficient; logPPGDP, propyleneglycol dipelargonate/water partition coefficient; log Pheptane/glycol, a non-aqueous partitioning system; SF, shake-flask; pH-metric, log P determination based on potentiometric titration in water and octanol/water; CPC, centrifugal partition chromatography; RP-HPLC, reversed-phase high performance liquid chromatography; TLC, thin-layer chromatography; ODS, octa-decylsilane; ABZ, end-capped silica RP-18 column; ODP, octade-cylpolyvinyl packing; IAM, immobilized artificial membrane; ILC, immobilized liposome chromatography; MEKC, micellar electrokinetic capillary chromatography.

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