Oral administration is still regarded as the most commonly accepted route of drug administration offering numerous advantages including convenience, ease of compliance, and cost-effectiveness. Not surprisingly, desirable oral bioavailability is one of the most important considerations for the successful development of bioac-tive molecules. Poor oral bioavailability affects drug performance and leads to high intra- and inter-patient variability.

The advent of combinatorial chemistry and high throughput screening in recent years have resulted in unfavorable changes in the molecular and physicochemical properties of drug candidates. Gaining sufficient understanding of the properties that impact oral bioavailability has become vitally important in designing new drug candidates and formulations that can successfully deliver them (Curatolo, 1998).

In the last few years, there have been numerous attempts to predict physico-chemical properties that are most desirable for a good drug candidate. Analysis of the structures of orally administered drugs, and of drug candidates, as pioneered by Lipinski and his colleagues (1997), has been the primary guide to correlating physicochemical properties with successful drug development candidates. Time-related differences in the physical properties of oral drugs have also been analyzed (Wenlock et al., 2003). These analyses have led to several sets of rules relating to lipiphilicity, molecular weight (MW), the number of hydrogen-bond donors and acceptors, polar surface area, and molecular rigidity as indicated by the number of rotatable bonds (Vieth et al., 2004).

While these rules provide good guidance in molecular design and lead optimization, the advances in the understanding of the causes of low oral bioavailability have led to significant improvements in drug delivery technologies.

This chapter summarizes the molecular and physicochemical properties that influence oral absorption and reviews the impact of these properties on the formulation strategies that can be applied to improve oral absorption.

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