Application of Acoustic- Vibratory Milling For Screening and Scale-Up of Micro/ Nanosuspensions in Early Drug Discovery and Development
Current methods of milling an active pharmaceutical ingredient (API) often suffer from limited control over particle size and solid-state form or require large amounts of material for optimization, rendering them unsuitable for use in early discovery efforts. We here develop operating workflows of an acoustic-vibratory milling technique, which enables both materials-sparing screens and scaled-up production of micro/nanosuspensions with well-defined and tunable particle size distributions. Workflows are based on the generation of guidance maps for API insensitive outputs (temperature) and API dependent outputs (particle size), with various operational parameters for milling such as container headspace, container geometry, milling media load & size, milling time, and excipient compositions. The
experimental conditions for low and high intensity milling were identified and implemented for six model compounds with a wide range of physicochemical properties, to conduct materials-sparing screens (10 mg) at high throughput (>36 conditions per run) and short milling times (2 hours) to successfully produce suspensions for all compounds tested. The scale-up capability of the approach is demonstrated for model API, mebendazole, by producing more than 20 g of suspensions per run with predefined size and solidstate form that corresponds to small-scale screens by two orders of magnitude. This work develops new tools that help enable micro/ nano-suspension development in early-drug discovery settings.