Sub-150 nm drug nanocrystals produced using a milligram-scale media mill

Nanocrystals (NCs), nano-sized drug particles, offer a promising strategy to enhance the bioavailability of poorly soluble compounds, a challenge that affects 70-90 % of new chemical entities. Among the available production methods, wet media milling is widely adopted due to its scalability and efficiency. However, conventional lab-scale mills often require large suspension volumes and high amounts of drug, limiting their suitability for early-stage development, particularly with novel or scarce compounds. This study introduces a miniaturised wet milling system (Mini Mill) capable of producing NCs using less than 15  mg of drug and standard laboratory equipment, such as Eppendorf® vials. The system was benchmarked against a well-established lab-scale milling method requiring approximately 100  mg of drug per trial. Three model drugs (itraconazole, acyclovir, and amphotericin B) were processed under optimised conditions. The Mini Mill yielded NCs with mean sizes of 107 ± 2 nm (itraconazole), 153 ± 37  nm (acyclovir), and 106 ± 14  nm (amphotericin B), all comparable to well-established lab-scale milling set-ups. Similarly, zeta potential measurements showed no significant differences between scales. Overall, the Mini Mill achieved an 85 % reduction in drug consumption without compromising key formulation attributes, positioning it as a practical and cost-effective tool for the early development of NCs-based formulations.