Plath Timo, Korte Carolin, Sivanesapillai Rakulan, Weinhart Thomas
Multi-Scale Mechanics, TFE, ET, MESA+, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands.
Process Technology Development, Engineering & Technology, Bayer AG, 51368 Leverkusen, Germany.
Pharmaceutics. 2021 May 1;13(5):645. doi: 10.3390/pharmaceutics13050645.
Twin-screw wet granulation is a crucial unit operation in shifting from pharmaceutical batch to continuous processes, but granulation kinetics as well as residence times are yet poorly understood. Experimental findings are highly dependent on screw configuration as well as formulation, and thus have limited universal validity. In this study, an experimental design with a repetitive screw setup was conducted to measure the effect of specific feed load (SFL), liquid-to-solid ratio (L/S), and inclusion of a distributive feed screw on particle size distribution (PSD) and shape as well as residence time distribution of a hydrophilic lactose/microcrystalline cellulose based formulation. An intermediate sampling point was obtained by changing inlet ports along the screw axis. Camera-based particle size analysis (QICPIC) indicated no significant change of PSD between the first and second kneading section, except for low L/S and low SFL where fines increase. Mean residence time was approximated as a bilinear fit of L/S and SFL. Moreover, large mass flow pulsations were observed by continuous camera measurements of residence time distribution and correlated to hold-up of the twin-screw granulator. These findings indicate fast granulation kinetics and process instabilities for high mean residence times, questioning current standards of two kneading compartments for wet granulation. The present study further underlines the necessity of developing a multiscale simulation approach including particle dynamics in the future.
双螺杆湿法制粒是从制药批次工艺向连续工艺转变过程中的关键单元操作，但目前对制粒动力学以及停留时间的了解仍然有限。实验结果高度依赖于螺杆配置和配方，因此普遍适用性有限。在本研究中，采用重复螺杆设置进行了实验设计，以测量特定进料负荷（SFL）、液固比（L/S）以及采用分配进料螺杆对基于亲水性乳糖/微晶纤维素配方的粒度分布（PSD）、颗粒形状以及停留时间分布的影响。通过沿螺杆轴线改变进料口获得了一个中间采样点。基于相机的粒度分析（QICPIC）表明，在第一和第二捏合段之间，PSD没有显著变化，但在低L/S和低SFL时细粉会增加。平均停留时间近似为L/S和SFL的双线性拟合。此外，通过对停留时间分布进行连续相机测量观察到较大的质量流脉动，并与双螺杆制粒机的持料量相关。这些发现表明，对于高平均停留时间，制粒动力学较快且过程不稳定，这对目前湿法制粒两个捏合区的标准提出了质疑。本研究进一步强调了未来开发包括颗粒动力学在内的多尺度模拟方法的必要性。
