room his serum level of phenytoin was “undetectable”; six months earlier, a routine
measurement had revealed a serum phenytoin level of 68μmol/L. He was given diazepam
5 mg intravenously (IV) and phenytoin 1,000 mg IV. His seizures soon abated. When
asked why he had stopped taking his phenytoin he stated that he had not, but had been
taking the same dose for years. His mother confirmed this story. She stated that he took
his daily dose of phenytoin every morning at breakfast and that she had witnessed his
doing so, every day for the past six years.
Upon questioning, it was discovered that this individual purchased his phenytoin in
bottles of 1,000 capsules, in order to save money. He routinely stored this phenytoin in
the basement of his home—a relatively damp and cool location—for months at a time;
one week earlier he had started to use the capsules from one of these old stored bottles.
When thirty “old” capsules from this recently opened bottle of 1000 capsules were
weighed, all had masses in excess of 295 mg. When thirty capsules from a recently pur-
chased supply of “new” phenytoin were weighed, all had masses less than 280 mg. An
examination of an old capsule revealed that the contents were hardened and slightly dis-
coloured. Subsequent analyses revealed that the phenytoin within the old capsules had
become excessively hydrated from the ambient humidity of their storage conditions.
The resulting hardened mass of drug material was less soluble within the gastrointesti-
nal tract and was thus less bioavailablefor absorption.
Many factors can influence the bioavailability of a drug molecule following oral
absorption. Damp storage conditions of the drug can cause increased molecular hydra-
tion with concomitant altered solubility. When a drug molecule is crystallized using dif-
ferent solvents or different conditions, the resulting change in crystal morphology can
influence bioavailability and thus alter biological results.
1.3 SHAPE (GEOMETRIC, CONFORMATIONAL, TOPOLOGICAL,
AND STERIC) PROPERTIES OF DRUG MOLECULES
Physicochemical properties are important in determining the ability of a drug molecule
to survive the pharmacokinetic phase and to reach the region of the receptor. The inter-
action of the drug molecule’s pharmacophore with its complementary receptor during
the pharmacodynamic phase of drug action is dependent upon a geometrically precise
and accurate intermeshing of two molecular fragments. A rigorous control of molecu-
lar geometry and shape is crucial to the drug design process. Knowledge of molecular
geometry also plays an important role in understanding quantitative structure–activity
relationships during drug optimization (see section 3.3.2).
1.3.1 Conformational Isomerism and Drug ActionThe concept of conformational isomerismis central to any consideration of molecular
shape. Molecules that are flexible may exist in many different shapes or conformers.
Conformational isomerism is the process whereby a single molecule undergoes transi-
tions from one shape to another; the physical properties of the molecule have not
changed, merely the shape. Conformational isomerism is demonstrated by compounds
in which the free rotation of atoms around chemical bonds is not significantly hindered.
The energy barrier to the transition between different conformations is usually very low
32 MEDICINAL CHEMISTRY