Advantages and Limitations of the CPC Method for log P Measurements

The CPC method is probably the most precise and accurate method existing thus far for partition coefficient measurements. The problems inherent in the SF method caused by the adsorption, instability, impurity and volatility of solutes, and the impurity of solvents are not at all disturbing in the CPC method. When using different phase volume ratios for the same compound, the differences in the obtained log P values are negligible. This novel method needs relatively short times for a measurement in comparison with the shake-flask method due to its efficient mixing. Furthermore, the amounts of samples needed for the measurement are minute and comparable with the RP-HPLC method. In principle, this technique can be automated using an autosam-pler and computer monitoring if no mechanical problems occur during the measurement; however, we have not tried this possibility yet.

a ci ch3

CI CH3

O" HN

CI CH3

ci ch3

Organic phase

Aqueous phase

cl ch3

cl ch3

Cl ch3

Figure 9. The interconversion, predominance, and conformational behavior of uncharged and zwitterionic raclopride in a biphasic system. In the aqueous phase at pH 7.4, raclopride exists predominantly at a zwitterionic state. The zwitterionic raclopride is, however, relatively unstable and converted to an uncharged form having two internal hydrogen bonds as suggested by its low Alog P value (0.5).

The CPC method has limitations of its own: the limited range of measurable log P values (-3 to 3) is a genuine one, but it concerns a small proportion of compounds of interest. While methods of different operational modes using Sanki CPC have been applied to measure highly lipophilic compounds [34], they were impracticable due to extremely long retention time (15 hours for a compound of log P = 3). In comparison with the RP-HPLC method, it consumes relatively large amounts of organic solvent when using the organic phase as the mobile phase and running at a flow-rate of 3-6 ml/ min. It should also be noted that mechanical expertise is highly desirable in order to maintain the functioning of the centrifuge, since the current engineering standards of the centrifuge have yet to be improved.

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