Dosage form design begins with suitable understanding of the biopharmaceutical characteristics of the therapeutic agent under consideration. While chemical and physical properties govern biological performance of a specific compound, it is often possible to modulate oral absorption through a variety of techniques to maximize the dissolution characteristics of the drug in the formulation. Following oral administration, drug substances are exposed to a range of pH conditions which impact the ionization state of drug molecules as they pass through the gastrointestinal tract. For poorly water soluble drugs, particle size control is important to enhance dissolution from the solid dosage form. Poorly soluble drugs containing weakly acidic chemical functionalities are subject to limited aqueous solubility under gastric pH conditions (i.e., pH < pKa). General strategies for overcoming limitations related to oral absorption will be highlighted. As examples, two weakly acidic compounds with relatively high pKa values (BMS-A and BMS-B) will be discussed. Both particle size reduction and salt formation were explored in order to achieve suitable blood levels. The in vitro dissolution characteristics of the various forms as well as the rate and extent of oral absorption were evaluated in a canine model, and the resulting plasma concentration-time profiles were simulated. While dissolution studies could often be used to rank-order in vivo performance in terms of oral exposure, the relative exposure of salt forms versus free acid forms could not be adequately predicted by simple in vitro dissolution experiments.