The active pharmaceutical ingredients (APIs) as well as excipients in a solid dosage form can take up water vapor both during manufacture and subsequent storage of the product. Uptake of unacceptable amount of water can cause adverse effects on physical and chemical stability of APIs and functionality of excipients. It is prudent to select drug candidates with low hygroscopicity to minimize the development risk and time. The objectives of this study are: (i) to investigate the risk in predicting long-term water uptake from short-term water sorption studies, (ii) to understand the thermodynamic and kinetic factors that affect water uptake by pharmaceutical crystals. Automated sorption microbalance (ASM) is often used to determine the hygroscopicity, in which the small sample size and gas purge are believed to accelerate the water sorption process so that equilibrium could be attained in a short time period. However, caution must be exercised when the rates of water vapor diffusion or heat transfer at the solid-vapor interface are not the limiting factors. Four cases are discussed in this thesis, in which ASM failed to predict long-term water uptake. 1) Water vapor was believed to diffuse into the lattice of a metastable crystalline form and induced a polymorphic transformation. The crystallization of the stable form led to a decrease in water content. 2) Adsorbed water formed a surface solution and enhanced the mobility of surface molecules. Nucleation rate of hydrate could be the rate-limiting step. 3) Water sorption induced a crystal to liquid crystal transformation in a surface-active compound, where the latter retains orientational but lacks positional order of molecular packing. 4) The formation of a metastable liquid crystalline phase was kinetically favored for amorphous materials formed in surface-active compounds. The metastable liquid crystalline phase was stable for 3 months when stored under ambient conditions.