Small-scale aqueous suspension preparation using dual centrifugation: the effect of process parameters on the sizes of drug particles

The dual centrifugation approach has in the recent years emerged as a powerful milling tool to prepare pharmaceutical suspensions in submicron range with a fast-milling capacity by milling 40 samples simultaneously in 2 mL vials. While there is some standardized milling conditions described in the literature when preparing aqueous suspensions with dual centrifugation, a more systematic and experimental understanding of the milling process to evaluate the impact of different process variables in the dual centrifuge on the final sizes of the suspended drug particles independent of the drug compound used was desired. Overall, the present study demonstrated the applicability of the dual centrifuge for small-scale screening purposes and showed the impact of process parameters on the physical attributes of prepared suspensions. In the present work, the rate of size reduction on three different model compounds, i.e., cinnarizine, haloperidol, and indomethacin, was found to be mostly influenced by the milling speed, size of milling beads, and the bead loading during milling, whereas the rotor temperature did not affect the particle size profiles when stabilized with polysorbate 20 during milling with dual centrifugation. Smaller particle sizes were in general obtained at the highest milling intensity, i.e., 1500 rpm, smallest bead size, i.e., 0.2 mm, and higher bead loadings (42 %, 56 %, and 83 %). The grinding limit of approximately 0.50 µm, 0.70 µm, and 0.35 µm for cinnarizine, haloperidol, and indomethacin, respectively, was achieved relatively fast, i.e., 30 min of milling at the specified conditions, compared to when suspensions were milled with larger bead sizes (i.e., 1.0 mm), lower milling intensities (e.g., 1000 rpm), and lower bead loadings (e.g., 14 or 28 %). The study further confirmed that a higher milling intensity was necessary during milling of haloperidol suspensions probably due to the compounds predominantly plastic properties. Sizes of indomethacin particles increased with longer milling runs up to 240 min and also higher bead loadings of 56 % and 83 %. These observations were further supported by the color conversion from white to yellow of indomethacin suspensions which indicated generation of small quantities of amorphic material after milling with a high milling intensity. Upscale investigations showed comparable particle size profiles for all three model compounds while milling at 1500 rpm for five minutes.