ABSTRACT
The widespread application of combinatorial chemistry and high-throughput screening in drug discovery that began in the early 1990s favors the selection of poorly water-soluble new chemical entities (NCEs), often making oral drug product development very challenging (1). A poorly water-soluble drug is defined as one for which the dissolution time of a single dose in the gastrointestinal (GI) fluids exceeds the normal transit time through the absorptive regions of the gastrointestinal tract (GIT) (2). The absorption of these compounds is dose-dependent and controlled by the dissolution rate in the GIT (3). Particle size reduction and salt formation, which are common strategies for improving dissolution rate, are not always successful at achieving the desired extent of absorption enhancement. There are practical limitations to the degree of particle size reduction achievable by conventional means, which limits the usefulness of this technique. Salt formation that requires an ionizable functional group on the pharmacophore, may not be feasible for very weakly acidic or basic compounds. Even when a salt is formed, it may prove ineffective to achieve the desired absorption enhancement due to pH-mediated precipitation of the drug in the GIT following initial dissolution. Attempts have been made to improve the absorption of poorly water-soluble compounds by solubilizing them in formulations. Such formulations that are typically liquid in nature, rely on micellar or solvent/cosolvent solubilization techniques, oil-in-water emulsions, pH-adjusted
solutions, or the use of complexing agents. However, the usefulness of these formulations can be limited by their inability to solubilize the entire drug dose in the volume of a single gelatin capsule suitable for oral administration. Solid dispersion formulations that may not require full solubilization of the drug in the excipient matrix can provide highly effective oral formulations of poorly water-soluble drugs, when the above-mentioned options fail.
