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This study focuses on the relationship between drug dissolution properties, physical stability against recrystallization, and specific mechanical energy (SME) from a hot melt extrusion (HME) process of ternary amorphous solid dispersions (ASDs) containing indomethacin (IND), HPMC and mesoporous silica (XDP) prepared using different HME screw condition (the number of kneading zones/rotation speed). The screw condition greatly influenced the amorphous characteristics of the processed material and SME values. The higher SME samples demonstrated a larger parachute effect in dissolution test and reduced the rate of recrystallization upon exposure to elevated temperature/humidity conditions, which can be explained from the enhanced miscibility and interactions of IND/HPMC/XDP. The molecular investigation by solid-state NMR (ssNMR) suggested that higher SME input produced better IND/HPMC miscibility and interaction. Interestingly, XDP showed distinct contacts with IND and HPMC in the high-SME samples. The IND-HPMC interaction is not sufficient to maintain a highly mixed ASD at a high drug load without the assistance of XDP. Therefore, SME is a critical parameter for predicting enhanced dissolution and physical stability of IND in ASDs. Moreover, multi-nuclear and multi-dimensional ssNMR provide mechanistic understanding of molecular properties and bring new perspectives for preparation, analysis, and applications of XDP as a pharmaceutical carrier.