Accelerated Formulation Development for Nanomilled Active Pharmaceutical Ingredients Using a Screening Approach

In order to enable the accelerated preclinical and clinical pharmaceutical development of formulations based on nanomilling, a screening media mill was developed and evaluated for the production of nanoparticulate active pharmaceutical ingredients (API). The screening media mill is based on the principle of a conventional planetary mill, equipped with up to 24 milling beakers of 0.05–1.0 mL individual milling chamber volume. The applicability of the screening media mill was evaluated by 0.7–12.8 mg naproxen (2 wt %) per batch with a nanomilling formulation known from the literature. A case study for the preclinical formulation development is presented, applying 42 screening experiments by one operator within 5 working days, using in total 110 mg API. Promising nanomilling formulations with median particle sizes below 200 nm could be identified, suitable for preclinical in vivo studies. A second case study for the early clinical development of another proprietary API showed the successful formulation development within 12 working days. Up‐scaling to a miniaturized stirred media mill of 10 mL milling chamber volume resulted in a satisfying comparability of the selected formulations, with varying performance. Further up‐scaling of the most promising formulation to a laboratory‐scale stirred‐media mill showed the successful production of 250 g API with a median particle size of 140 nm. A screening media mill is presented for the accelerated formulation development of nanomilled active pharmaceutical ingredients which can operate up to 24 experiments in parallel with batch sizes down to 1 mg. The systematic screening of nanomilling formulations is shown by two case studies. Selected nanomilling formulations were also investigated regarding up‐scaling using a miniaturized and a laboratory‐scale stirred media mill.