The aim of our work was to study and define a computationally-based adiabatic scale-up methodology for a hot-melt extrusion (HME) process to produce an amorphous solid dispersion (ASD). As a drug product becomes commercially viable, there is a need for scaling up the manufacturing process. In the case of HME used for the formation of ASDs, scale-up can be challenging due to the fundamental differences in how heat is generated in extruders of differing scale, i.e. conduction vs. viscous dissipation and the significant role heat generation plays in determining the final product attributes. Using a 30%w/w dipyridamole-in-copovidone formulation, 11 mm-, 16 mm- and 24 mm-diameter extruders with L/D 40, solid-state characterization tools, a geometric scaling equation, and Ludovic® twin-screw extrusion software, we compared the total imparted material energy, the conducted energy and the difference between barrel and melt temperature at die exit for various feed rates and screw speeds. Numerical simulation identified desirable adiabatic conditions at multiple extruder scales in agreement with the chosen scaling factor. With the use of computational tools, the energetics in an extrusion process can be evaluated and processing conditions can be selected to identify the most efficient scaling of a HME process.