pharmacological reactions. Theoretically, there are no absolutely insoluble compounds;
every molecule is soluble in both the aqueous and nonaqueous lipid “compartments” of
a cell. The degree of solubility, however, differs between each compartment. The pro-
portion of these concentrations at equilibrium—or the ratio of solubilities—is called the
partition coefficient; partition coefficients are extremely important when understanding
the properties of drug molecules. Most successful drugs exhibit solubility to some extent
in both water and lipid environments.
Solubility is a function of many molecular parameters. Ionization, molecular struc-
ture and size, stereochemistry, and electronic structure all influence the basic interac-
tions between a solvent and solute. As discussed in the previous section, water forms
hydrogen bonds with ions or with polar nonionic compounds through -OH, -NH, -SH,
and -C=O groups, or with the nonbonding electron pairs of oxygen or nitrogen atoms.
The ion or molecule will thus acquire a hydrate envelope and separate from the bulk
solid; that is, it dissolves. The interaction of nonpolar compounds with lipids is based
on a different phenomenon, the hydrophobic interaction, but the end result is the same:
formation of a molecular dispersion of the solute in the solvent.
Although successful drugs tend to exhibit solubility in both aqueous and lipid envi-
ronments, there are a few examples in which solubility in only one of these phases cor-
relates with pharmacological activity. One such example is the local anesthetic activity
ofp-aminobenzoic acid esters, which is partly proportional to their lipid solubility.
Another thoroughly investigated example is the bactericidal activity of aliphatic alco-
hols. In the homologous series beginning with n-butanol and ending with n-octanol, the
bactericidal activity changes with increasing molecular weight. Whereas n-butanol and
n-pentanol are active against Staphylococcus aureus, higher members of the series fail
to kill the bacteria because the necessary concentration cannot be reached, arising from
solubility considerations.
DRUG MOLECULES: STRUCTURE AND PROPERTIES 27Figure 1.7 Effects of hydration on a drug molecule: A drug molecule does not exist in a
vacuum; it is hydrated. In order to interact with its receptor, it must be dehydrated. Water mole-
cules hydrogen-bond to the functional groups of the drug molecule. Additional water molecules
then hydrogen-bond to these inner water molecules. The overall result consists of many layers of
hydration.