Use a microcalorimetric technique to measure the interactions between water vapor and amorphous pharmaceutical solids and describe the relationship between long-term physical stability and the storage relative humidity (RH) at constant temperature. A thermal activity monitor was used to characterize interactions of water vapor with spray-dried amorphous sucrose, lactose, raffinose, and sodium indomethacin. Differential scanning calorimetry was used to measure glass transition temperature, Tg. X-ray powder diffraction was used to confirm that the spray-dried samples were amorphous. Scanning electron microscopy was used to examine particle morphology. Specific surface area was determined by BET analysis of nitrogen and krypton adsorption isotherms. The moisture-induced thermal activity traces (MITATs) of the materials in this study exhibit general behavior that helps explain the effect of moisture content on the physical stability of the glassy phase at a given storage temperature. At some RH threshold, RHm, the MITAT exhibits a dramatic increase in the energy of interaction between water vapor and the glass that cannot be explained by a phase or morphology change. Calorimetric data indicate that water vapor-solid interactions are reversible below RHm; above RHm, energetic hysteresis is observed and water-water interactions predominate. In addition, the MITAT was deconvoluted into sorptive and nonsorptive components, making it possible to assign the observed heat flow to unique thermal events. Samples stored at a RH just below RHm for more than 2 months show no evidence of morphology or phase change. In addition, the MITAT can be deconvoluted into sorptive and nonsorptive components by using a twin-calorimeter arrangement. This analysis provides specificity to the microcalorimetric analysis and helps explain the nature of the physical changes that occur during the hydration glassy phase. The MITAT is a useful tool to determine the onset of moisture-induced physical instability of glassy pharmaceuticals and may find a broad application to determine appropriate storage conditions to ensure long-term physical stability.