Control of temperature rise during wet stirred media milling

Abstract

Temperature increases during wet stirred media milling (WSMM) significantly, which may cause degradation of thermolabile drugs. This study aims to examine the impacts of batch size, pre-cooling, and cooling rate on product temperature under various milling conditions. To this end, a lab-scale mill was used along with a small batch (∼0.22 L) and a large batch (∼5.4 L) of CaCO₃ suspension. For the 5.4 L batches, the impacts of stirrer speed and bead loading–size on particle size and temperature were investigated experimentally and simulated by an enthalpy balance model (EBM). Our results suggest that the median size was lower (median size x₅₀ as low as 0.227 µm), and the temperature was higher (with the maximum temperature rise of 27 °C) at the higher stirrer speed with a higher bead loading, whereas the bead size impact was weak. The temperature rise was 4–8 °C lower for the smaller batch than for the larger batch. Besides predicting the milling parameters’ impacts, the EBM suggests that lowering coolant temperature was the most effective to control product temperature, whereas a low suspension flow rate could be detrimental, and pre-cooling had limited favorable impact. Overall, we conclude that batch size, coolant temperature, pre-cooling, and suspension flow rate can be adjusted, as guided by EBM, to control temperature during WSMM. These findings offer practical guidance for controlling thermal conditions in WSMM and improving scalability and product quality in pharmaceutical manufacturing.