Mechanochemistry Applied to the Synthesis of X-ray Contrast Agent

Mechanochemical activation in planetary ball mills generates energy that is effective for the efficient, solvent-free syntheses of several types of organic molecules, including active pharmaceutical ingredients and diagnostic agents. X-ray-based procedures are the most commonly used of all diagnostic imaging techniques, because they offer several advantages, such as deep penetration, high resolution, and low cost. Iodinated X-ray contrast agents have long been used in medicine to facilitate and improve the acquisition of images by radiographic modalities. Iopamidol was the first agent developed in the field of nonionic X-ray contrast agents for imaging diagnosis and is still one of the most frequently used worldwide. We herein report an experimental investigation aimed to design a mechanochemical synthesis of Iopamidol, with the double goals of process intensification and either the elimination or significant reduction of the use of the high-boiling-point and reprotoxic solvent N,N-dimethylacetamide. The greener wet milling protocol gave Iopamidol in higher yields using safer solvents such as acetonitrile and N,N-dimethyloctanamide.