Drug Liposome Partitioning First Look

Fig. 18 shows lipophilicity plots for three drug substances: ibuprofen, propranolol, and hydroxyzine, in octanol/water (dotted curves) and multilamellar liposome/water (solid curves). The research is jointly pursued with Leo Herbette and his coworkers and will be the subject of a future publication. Noteworthy is the effect of cholesterol on the partitioning of ibuprofen into the liposomes, as shown in the figure.

We have described in a very comprehensive way the experimental and mathematical characteristics of the lipophilicity profile. The benefits of the pH-metric technique for the thorough assessment of the lipophilicities of a large variety of molecules are substantial. In an hour or so a whole lipophilicity profile for a drug substance can be determined, often with very high precision. We have reliably measured pKas as high as 13.3 and as low as 0.6, log P as high as 7.4 and as low as -2.3. The span in log P is nearly ten orders of magnitude! For example, the complete lipophilicity profile of chlorproma-zine, which has a log P 5.40, can be determined reliably in about 40 minutes. Factors limiting the measurement of log P >7 include (a) extreme water insolubility, (b) poorly reproducible micelle or other type of aggregation reactions, and (c) surface activity of the substance. Hydrophilic molecules are very difficult to characterize by the technique if their log P is less than -2, the approximate limit of detection. The log P region between -1.5 and -2 is difficult for the pH-metric technique and care is required in the design of the assay.

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