Approaches for Improving Bioavailability of Poorly Soluble Drugs

Poorly water-soluble drug candidates often emerge from contemporary discovery programs 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%), interand 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 pharmacologic 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). The relative importance of poor solubility and permeability towards poor oral absorption depends on the research approach used for lead generation. As Lipinski (2) pointed out, a “rational drug design” approach leads to time-dependent higher molecular weight, higher H-bonding properties, unchanged lipophilicity, and therefore, poorer permeability. A high throughput screening (HTS)-based approach leads to high molecular weight, unchanged H-bonding properties, higher lipophilicity, and, hence, poorer aqueous solubility. Despite great efforts in rational drug design, pharmaceutical scientists are often confronted with resolving bioavailability of poorly soluble compounds. Considering the principle of drug absorption by a passive transport mechanism