The amidation reaction is a key step for the preparation of a large number of organic molecules, including active pharmaceutical ingredients (APIs), but still challenging from the point of view of its efficiency and sustainability. In this context, the solventless synthesis of an amide, starting from a carboxylic acid and an amine, was performed in a twin-screw extruder (TSE) in the presence of a coupling agent, providing a high yielding and productive method. Reaction conditions were evaluated and successfully used to prepare two APIs, teriflunomide and moclobemide. This complements the synthetic tool box of twin-screw extrusion to prepare organic molecules and opens the way to broader applications, including in an industrial perspective.