Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark.
NETZSCH-Feinmahltechnik GmbH, Sedanstrasse 70, 95100 Selb, Germany.
Int J Pharm. 2024 Dec 5;666:124760. doi: 10.1016/j.ijpharm.2024.124760. Epub 2024 Sep 25.
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.
在药物开发的早期阶段，通常使用少量的药物化合物，特别是对于需要大量筛选调查来确定最终配方组成的药物，例如纳米和微悬浮液。出于这个原因，近年来，双离心方法由于其可重复性和快速研磨能力而被使用，它可以在 2 毫升小瓶中同时处理 40 个样品，而不需要由于内置冷却系统而添加冷却中断。尽管如此，在高强度研磨过程中热量可能会散发到样品中，导致样品温度升高，这可能会影响热敏化合物，并可能影响筛选实验中获得的悬浮液，如果所用稳定剂在性能上存在与温度相关的变化。因此，在本研究中，系统研究了双离心方法在研磨过程中不同工艺参数对样品散热的影响。研究发现，研磨速度对最终样品温度的影响最大，但其他参数，如研磨珠装载量、研磨珠尺寸和研磨过程中的放置位置，也显著影响了研磨介质的最终平均温度。较高的温度是通过较高的研磨珠装载量获得的，即 3000 毫克研磨珠/毫升和研磨速度（1500 转/分），以及在生产过程中使用较小的研磨珠，即 0.1 毫米。该研究还表明，在研磨过程中位于底部圆盘上的样品和位于样品圆盘外部位置的样品测量到的温度更高。放大研究表明，当样品以类似的配方参数和研磨速度制备时，样品温度会大大升高（几乎接近沸点）。此外，该研究表明，与仅含有纯化水的样品相比，在悬浮液制备过程中添加药物化合物会降低最终样品温度，这是由于药物化合物的能量吸收。
