partition coefficients, and to simplify the determination of P values for small molecules.
The fragmental constants are determined statistically by regression analysis; they are
additive, and their sum provides a reasonable value for logP. Detailed tables of the fvalues
for various functional groups have been published by Rekker (1977) and are sometimes
used in computer program algorithms that calculate logP values. Somewhat analogous
to the fragmental constants are the atomic constants put forth by Ghose and Crippen
(1986); these assign logP values for every atom in a molecule and then determine the
logP for the overall molecule by summing these values. Currently, there are a number of
computer programs available (e.g., cLogP) for calculating logP values. In addition to these
theoretical methods for calculating logP, there are a number of experimental protocols,
including the classical “shake flask” method, and various chromatographic techniques,
including HPLC methods.
1.2.4 Surface Activity Effects of Drug MoleculesAlthough a capacity to cross biological membranes and barriers is important for most
drugs, there are also pharmaceutical agents that display mechanisms of action that are
more dependent upon activities at surfaces. Pharmacologic reactions may occur on bio-
logical surfaces and interfaces. The energy situation at a surface differs markedly from
that in a solution because special intermolecular forces are at work; therefore, surface
reactions require specific consideration. In living organisms, membranes comprise the
largest surface, covering all cells (the plasma membrane) and many cell organelles (the
nucleus, mitochondria, and so forth). Dissolved macromolecules such as proteins also
account for an enormous surface area (e.g.,1 ml of human blood serum has a protein
surface area of 100 m^2 ). Biological membranes also (i) serve as a scaffold that holds a
large variety of enzymes in proper orientation, (ii) provide and maintain a sequential
order of enzymes that permits great efficiency in multistep reactions, and (iii) serve as
the boundaries of cells and many tissue compartments. In addition, many drug receptors
are bound to membranes.
It is therefore apparent why the physical chemistry of surfaces and the structure
and activity of surface-active agents are also of interest to the medicinal chemist.
Antimicrobial detergents and many disinfectants exert their activity by interacting with
biological surfaces and are important examples of surface-active drug effects.
1.2.4.1 Surface Interaction and Detergents
All molecules in a liquid phase interact with each other and exert a force on neighbor-
ing molecules. We have already discussed the hydrogen-bonding interaction of water
molecules that creates clusters. The water molecules at a gas–liquid interface, however,
are exposed to unequal forces, and are attracted to the bulk water of the liquid phase
because no attraction is exerted on them from the direction of the gas phase. This
accounts for the surface tension of liquids.
Because the dissolution of a solid is the result of molecular interaction between a
solvent and the solid (which, once dissolved, becomes a solute), polar compounds capable
of forming hydrogen bonds are water soluble, whereas nonpolar compounds dissolve
only in organic solvents as the result of van der Waals and hydrophobic bonds. Compounds
30 MEDICINAL CHEMISTRY