Zulbeari Nadina, Lund Nanna Einshøj, Holm René
Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Campusvej 55 5230, Odense, Denmark.
Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Campusvej 55 5230, Odense, Denmark.
Eur J Pharm Sci. 2025 Feb 1;205:106980. doi: 10.1016/j.ejps.2024.106980. Epub 2024 Dec 4.
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.
近年来，双离心法已成为一种强大的研磨工具，可通过在2 mL小瓶中同时研磨40个样品，以快速研磨能力制备亚微米级的药物混悬液。虽然文献中描述了使用双离心法制备水性混悬液时的一些标准化研磨条件，但人们希望对研磨过程有更系统的实验理解，以评估双离心机中不同工艺变量对悬浮药物颗粒最终尺寸的影响，而不考虑所使用的药物化合物。总体而言，本研究证明了双离心机适用于小规模筛选目的，并显示了工艺参数对制备的混悬液物理属性的影响。在本工作中，发现三种不同模型化合物（即桂利嗪、氟哌啶醇和吲哚美辛）的粒径减小速率主要受研磨速度、研磨珠尺寸和研磨过程中的珠粒装载量影响，而在双离心研磨过程中用聚山梨酯20稳定时，转子温度不影响粒径分布。一般来说，在最高研磨强度（即1500 rpm）、最小珠粒尺寸（即0.2 mm）和更高珠粒装载量（42%、56%和83%）下可获得更小的粒径。与使用较大珠粒尺寸（即1.0 mm）、较低研磨强度（例如1000 rpm）和较低珠粒装载量（例如14%或28%）研磨混悬液相比，桂利嗪、氟哌啶醇和吲哚美辛分别在约0.50 µm、0.70 µm和至0.35 µm的研磨极限在相对较短时间内（即在指定条件下研磨30分钟）即可达到。该研究进一步证实，在研磨氟哌啶醇混悬液时需要更高的研磨强度，这可能是由于该化合物主要具有塑性特性。吲哚美辛颗粒的尺寸随着研磨时间延长至240分钟以及更高的珠粒装载量（56%和83%）而增大。吲哚美辛混悬液从白色变为黄色的颜色转变进一步支持了这些观察结果，这表明在高研磨强度研磨后生成了少量无定形物质。放大研究表明，在1500 rpm下研磨五分钟时，所有三种模型化合物的粒径分布具有可比性。
