Partitioning Into Octanol

In all other sections of this book, we use the term Kp to represent the partition coefficient and Kd, the apparent partition coefficient. These terms were chosen to avoid symbol conflict when discussing permeability and diffusivity. Since this chapter and Chapter 5 are devoted primarily to partition coefficients, we will use the most common terminology: P for partition coefficients and D for apparent (pH-dependent) partition coefficients. [Other symbols for these parameters have been used in the literature, including POW (oil-water partition), KOW, PC, and APC.]

Central to the Hansch analysis [17,98] is the use of log P or log D to predict biological activity. Much literature has been published about the measurement and applications of these parameters [17,23,24,57,98-100,224,225,243,245-265]. Two conferences have been dedicated to the topic [266,267]. Several studies [245,246,268] describe how to measure log P= log D: which techniques to use, what pitfalls to look out for, what lipid : water volumes to consider, the value of GLP—in other words, how to do it right. The structure of octanol became better understood [99,100]. Issues of water drag were investigated [247,248]. Partition solvents other than octanol (CHCl3, various alkanes, PGDP, and 1,2-dichlor-oethane) were explored for the effect of their hydrogen bonding donor/acceptor properties [17,151,249,261,269]. Seiler's [250] concept of A log P was further tested [251,252,257]. Methods to predict H-bond factors from two-dimensional structures were expanded [254-260]. Hydrogen bonding was prodded as "the last mystery in drug design'' [253]. The concept of "molecular chameleons," proposed by Testa and others, was applied to the study of intramolecular effects

Absorption and Drug Development: Solubility, Permeability, and Charge State. By Alex Avdeef ISBN 0-471-423653. Copyright © 2003 John Wiley & Sons, Inc.

in morphine glucuronide conformational-sensitive partitioning [151,262,263]. A case was made for the return of olive oil, as a model solvent in the prediction of partitioning into adipose tissue [264].

Today almost every practicing pharmaceutical scientist knows the difference between log P and log D [229,270-276]. Better understanding of the partitioning behavior of ampholytes and charged species emerged [277-291]. The concept of the micro-log P was formalized [224,243,273,275]. Rapid high-performance liquid chromatography (HPLC) methods for determining log P were fine-tuned [292-298]. Immobilized artificial membrane (IAM) chromatography [47,299-311], liposome chromatography [312-319], and capillary electrophoresis [320-322] evoked considerable interest. An accurate (compared to shake-flask) and fast (2h) method using dialysis tubing to separate the aqueous phase from the octanol phase was reported [323]. Potentiometric methods of log P determination matured and achieved recognition [25,112,149-151,153,161,162,166,172,224,225,250,268,269, 275,324-363]. Some remarkable new insights were gained about the membrane interactions of charged amphiphilic species from the study of drug partitioning into liposomes (Chapter 5). The need for high-throughput measurements led to the scaling down of several techniques to the 96-well microtiter plate format [294].

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