A novel temperature-controlled media milling device to produce drug nanocrystals at the laboratory scale

Poor aqueous solubility of preexisting and emerging drug molecules is a common issue faced in the field of pharmaceutics. To address this, particle size reduction techniques, including drug micro- and nanonisation have been widely employed. Nanocrystals (NCs), drug particles with particle sizes below 1 µm, offer high drug content, improved dissolution, and long-acting capabilities. Media milling is the most used method to prepare NCs using of-the-shelf machinery, both at the laboratory and industrial scales. However, early NCs development, especially when limited amounts of the active are available, require the use of milligram-scale media milling. This study introduces a novel mini-scale milling device (Mini-mill) that incorporates temperature control through a water-cooled jacket. The device was used to produce NCs of three model hydrophobic drugs, itraconazole, ivermectin and curcumin, with lowest particle sizes of 162.5 ± 0.4 nm, 178 ± 2 nm, and 116.7 ± 0.7 nm, respectively. Precise control of milling temperature was achieved at 15, 45, and 75°C, with drug dependent particle size reduction trends, with no adverse effects on the milling materials or polymorphic changes in the NCs, as confirmed by calorimetric analysis. Finally, a scale-up feasibility study was carried out in a lab-scale NanoDisp®, confirming that the novel Mini-mills are a material-efficient tool for early formulation development, with potential for scale-up to commercial mills.