Solid-state characterization plays a vital role in lead optimization and candidate selection with the appropriate physicochemical properties for proper oral dosage formulation. Aqueous solubility is an important parameter in the successful development of oral dosage formulation since poor aqueous solubility limits absorption. In this study, we summarized an efficient approach using a small amount of sample for solid-state characterization, including thermodynamic solubility, which is defined as physicochemical profiling. By using the physicochemical profiling results of 75 anti-cancer drugs and clinical candidates, we examined the relationship between thermodynamic solubility and molecular structural parameters and assessed the effects of thermodynamic solubility on pharmacokinetic profile for rational soluble drug design. The Log D_pH 7.4, aromatic ring count, and hydrogen bond count were good indicators for predicting sparingly soluble compounds that increase the lattice energy because of π–π stacking and hydrogen bonds, resulting in lowered thermodynamic solubility. The level of thermodynamic solubility in simulated intestinal fluid (pH 6.8) in the presence and absence of bile acid, which is required for minimal acceptable bioavailability (>30%), was 1 µg/mL and 10 µg/mL, respectively. Physicochemical profiling, which includes thermodynamic solubility considering its solid-state properties, contributes to rational lead optimization and efficient candidate selection for drug development.