ABSTRACT
Poorly water-soluble drug candidates often emerge from contemporary discovery pro-
grams and present formulation scientists with considerable technical challenges. With the
advent of combinatorial chemistry and high throughput screening, the number of poorly
water-soluble compounds has dramatically increased. The absorption and bioavailability
of such compounds when presented in the crystalline state to the gastrointestinal tract is
poor and variable. Bioavailability is clinically important because pharmacologic and toxic
effects are proportional to both dose and bioavailability. When bioavailability is very low
(e.g., < 20%), inter-and intra-subject variability in bioavailability are magnified and incomplete oral bioavailability can become a great concern. The consequence of low and
variable bioavailability is substantially difficulty in predicting and controlling the phar-
macologic and toxic effects of a given dose. This is especially true when drugs have steep
dose-effect curves or narrow safety margins. The poor solubility or pH-dependent
solubility also generally causes significant food effects, which also limits the flexibility
that a patient may like to have while taking a medicine. Cost may be another driving force
for some compounds. If bioavailability averages 20%, for example, then 80% of a dose is
wasted. Maximizing bioavailability contributes to increasing cost-effectiveness (1).
