Dieyi Lenora, Guner Gulenay, Chattoraj Sayantan, Morrison Christopher
Process Engineering and Analytics, Drug Product Development, GSK R&D, Upper Providence, PA, USA.
Process Engineering and Analytics, Drug Product Development, GSK R&D, Upper Providence, PA, USA.
J Pharm Sci. 2025 Apr 18;114(7):103798. doi: 10.1016/j.xphs.2025.103798.
This study investigates the impact of entrained air on the efficiency of wet bead milling within pharmaceutical development, using two aqueous nanosuspension formulations as case studies. Aqueous formulations of hydrophobic active pharmaceutical ingredients (APIs) are routinely employed in wet bead milling to develop therapeutic nanosuspensions which modulate drug release. However, these formulations can present significant manufacturing challenges, many of which may be directly caused or exacerbated by air entrainment. In addition to investigating how entrained air impacts wet bead milling process robustness and efficiency, this study explores methods of monitoring air entrainment using real time measurements of attributes, such as the slurry density, dissolved oxygen, and slurry height. The drug products were milled under comparable process conditions at two distinct scales. Half of the batches underwent a deaeration process, while the other batches served as controls without deaeration. Particle size measurements from the samples taken at predefined timepoints during milling reveal that aeration impedes the milling process, causing a lag in particle attrition that becomes particularly significant as the batch volume to chamber volume (batch-to-chamber) ratio increases. Our work addresses a key gap in the mechanistic understanding of the impact of air entrainment on wet bead milling efficiency. The findings will contribute to the design of more robust and efficient wet bead milling processes and the selection of scalable process analytical tools for monitoring air entrainment during nanosuspension manufacturing at a large scale.
本研究以两种水性纳米混悬液制剂为案例研究，调查夹带空气对药物研发中湿珠磨效率的影响。疏水性活性药物成分（API）的水性制剂通常用于湿珠磨，以开发调节药物释放的治疗性纳米混悬液。然而，这些制剂可能带来重大的制造挑战，其中许多可能直接由空气夹带引起或加剧。除了研究夹带空气如何影响湿珠磨工艺的稳健性和效率外，本研究还探索了使用实时测量属性（如浆料密度、溶解氧和浆料高度）来监测空气夹带的方法。药物产品在两种不同规模的可比工艺条件下进行研磨。一半批次进行了脱气处理，而其他批次作为未脱气的对照。在研磨过程中在预定义时间点采集的样品的粒度测量结果表明，通气会阻碍研磨过程，导致颗粒磨损滞后，随着批次体积与腔室体积（批次与腔室）比的增加，这种滞后变得尤为显著。我们的工作填补了对空气夹带对湿珠磨效率影响的机理理解方面的关键空白。这些发现将有助于设计更稳健、高效的湿珠磨工艺，以及选择可扩展的过程分析工具，以在大规模纳米混悬液制造过程中监测空气夹带。
