*2.1. Top-Down Production Approaches*

High-energy mechanical forces are involved in top-down approaches and are provided by media milling (MM) techniques, including NanoCrystals® or high-pressure homogenization (HPH), Insoluble Drug Delivery—Particles (IDD-P™), DissoCubes®, and Nanopure®, to comminute large crystals into crystals of smaller dimensions [16,44]. Topdown processes are commonly used for the preparation of crystalline nanoparticles [45] and are flexible following scale-up production [46]. Consequently, the process has been widely adopted for commercial scale preparation of nanocrystals. With the exception of Triglides produced by IDD-P®, the majority of the other products are commercially produced using NanoCrystals®. However, high-energy input, lengthy operational units, and the potential to introduce contamination from the use of grinding media are drawbacks of this technology. For instance, high pressures of up to 1700 bar with 50–100 cycles of homogenisation are often required to achieve a desired particle size distribution and size [3,47]. Furthermore, the milling time varies from hours to days depending on the

properties of the API, milling media, and extent of required particle size reduction [46,48]. Since contamination from grinding media may lead to unexpected side-effects and/or toxicities, the top-down production method is not a suitable option for the preparation of parenterally administered NC [49,50].
