Among novel drug-delivery systems, oral dispersible tablets which are solid dosage forms that disintegrate rapidly in the oral cavity within 1 min, are gaining importance due to their quick acceptance by patients, especially young children, and veterans. These tablets can be produced using hot-melt extrusion, where the formulations are extruded 20-40 °C above their glass transition temperature (Tg). Typically, polymers, such as poly(vinylpyrrolidone) copolymers or PVP, are added to formulations to prepare them for hot extrusion by reducing their Tg and melt viscosity. However, these polymers tend to cake under various environmental conditions, such as relative humidity (RH), temperature, and mechanical stress, which is detrimental to process efficacy. In this work, we are developing an approach to predict the caking behavior of these polymers with respect to relative humidity, temperature, and stress using state-of-the-art, in-situ techniques including dynamic vapor sorption (DVS), thermal analysis, tomography, power flow rheometry, and mechanical testing methods. The PVP was selected as the model polymer to test these methods. The tomography resulted showed that the PVP cakes form due to the coalescence of PVP particles following water sorption-induced plasticization. The temperature-dependent critical glass transition RH was measured using DVS. At 25 °C, the critical RH was determined as approximately 65%. The powder flow properties and mechanical testing results showed that the PVP caking is caused by the irreversible adhesion of the PVP particle induced by moisture-driven phase change. In the future, we will apply these techniques to evaluate the caking performance of a wide variety of moisture-sensitive polymers, and other powders, thus assessing the stability and process performance of complex formulations in pharmaceutical and chemical industries.