Temperature mapping of milling by dual centrifugation: A systematic investigation.

Using low quantities of drug compounds is often favorable in the early stages of drug development, especially for what require a large screening investigation to define the final formulation composition, such as nano- and microsuspensions. For that reason, the dual centrifugation approach has in the recent years been used due to its reproducible and fast-milling capacity with 40 samples in 2 mL vials simultaneously without the addition of cooling breaks due to a built-in cooling system. Nonetheless, heat can be dissipated into the samples during high-intensity milling, resulting in increased sample temperatures that potentially can affect thermolabile compounds and potential influence the obtained suspensions in the screening experiments if the used stabilizer has temperature dependent variations in the performance. Hence, a systematic investigation of the influence of different process parameters on the heat dissipation in samples during milling by the dual centrifugation approach was performed in the present study. It was found that the milling speed had the highest impact on the final sample temperature, but also other parameters, such as the bead loading, bead size, and placement in the centrifuge during milling had significantly influenced the final mean temperature of the milling media. Higher temperatures were obtained with higher bead loadings, i.e., 3000 mg milling beads/mL and milling speeds (1500 rpm), and when smaller milling beads, i.e., 0.1 mm, were used during production. The study further showed that higher temperatures were measured for samples located on the bottom disk during milling, and also when located on the outer placement on the sample disk. Upscale investigations showed immensely increased sample temperatures (almost up to boiling point) when samples were prepared under similar formulation parameters and milling speed as small-volume vials. Furthermore, the study indicated that the addition of drug compounds during suspension preparation decreased the final sample temperature compared to samples that only contained purified water due to energy absorption of the drug compound.