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In this study, a molecular dynamics simulation technique was employed to predict miscibility and interaction of Active Pharmaceutical Ingredient (API) with polymer carriers in solid dispersion system based on Hansen solubility parameter and hydrogen bond formation, respectively. Several APIs with and without hydrogen bonding tendency were studied. The Hansen solubility parameters of APIs and polymers calculated by molecular dynamic simulation were similar to reported values in the literature. Our simulation results were able to determine the interactions between APIs and various polymers (ionic and nonionic) and also predict the hydrogen bond interaction energy and hydrogen bond lifetime. The simulation results were verified by preparing solid dispersions using hot melt extrusion. As predicted by our simulation, clear and colorless extrudates were obtained for ibuprofen/PVP-VA 64, ibuprofen/Eudragit EPO, and fenofibrate/PVP-VA 64, which confirmed the miscibility between APIs (ibuprofen, fenofibrate) and polymers. Stability studies confirmed the amorphous stabilization of ibuprofen/PVP-VA64 and ibuprofen/Eudragit EPO solid dispersions. However, recrystallization of fenofibrate was observed from fenofibrate/PVP-VA 64 due to the lack of molecular interactions between fenofibrate and PVP-VA 64 as predicted in our simulation. This suggests that miscibility alone cannot be used to predict the stability of amorphous dispersion but molecular interactions have to be considered. The simulation method used in this study could be a useful tool for the selection of polymer excipients to form stable amorphous solid dispersions with enhanced performance.