Medicinal Chemistry

that are amphiphilic(i.e., containing hydrophobic as well as hydrophilic groups) will
concentrate at surfaces and thereby influence the surface properties of these interfaces.
Only in this way can amphiphilic detergents, through their hydrogen bonding with
water and nonpolar interaction with a nonpolar (organic) phase or with air, maintain an
orientation that ensures the lowest potential energy at an interface. A classic example of
such behavior is given by soap, a mixture of alkali-metal salts of long-chain fatty acids.
Figure 1.8 shows the interaction of soap molecules at an oil–water boundary; the circle
symbolizes the anionic carboxylate or the polar “head group,” and the zigzag line rep-
resents the hydrophobic alkyl chain.
A detergent-like soap forms a colloidal solution. At a very low concentration, soap mol-
ecules will be dissolved individually. At a higher concentration, the molecules find it more
energy efficient to “remove” their hydrophobic tails from the aqueous phase and let them
interact with each other, thus forming a miniature “oil drop” or nonpolar phase, with the
polar heads of the soap molecules in the bulk water. At a concentration that is characteris-
tic for a given individual detergent, molecular aggregates, known as micelles,are formed.
They are often spherical colloidal particles, but can also be cylindrical. The concentration
at which such micelles are formed is called the critical micellar concentration, and can
be determined by measuring the light diffraction of the solution as a function of detergent
concentration. The diffraction will show a sudden increase when micelles begin to form.
When soap is dispersed in a nonpolar phase, inverted micelles are formed in which the
nonpolar tails of the soap molecules interact with the bulk solvent while the hydrophilic
heads interact with each other. This behavior of amphiphilic molecules explains how they
can disperse nonpolar particles in water: the hydrocarbon tail of the amphiphile interacts
with the particle, such as an oil droplet, dirt, or a lipoprotein membrane fragment, covers
the particle, and then presents its hydrophilic head groups to the aqueous phase.

1.2.5 The Clinical–Molecular Interface: Bioavailability

and Drug Hydration

One of the authors recently encountered a 21-year-old male presenting to the emer-
gency room in status epilepticus (prolonged, uncontrolled seizures). This patient had a
seven–year history of epilepsy, well controlled with the drug phenytoin at a dose of
300 mg/day. Indeed, he had not experienced a seizure in more than a year. In the emergency

DRUG MOLECULES: STRUCTURE AND PROPERTIES 31

Figure 1.8 Micellar structure of a soap molecule on an oil–water interface. The nonpolar alkyl
chains are in the nonpolar phase; the polar carboxylate head groups are in the aqueous phase.