Wade J B, Martin G P, Long D F
Technical Services/Manufacturing Science Division, Eli Lilly & Company, Indianapolis, IN 46285, USA.
King's College London, Institute of Pharmaceutical Science, London SE1 9NH, UK.
Int J Pharm. 2015 Jan 30;478(2):439-46. doi: 10.1016/j.ijpharm.2014.11.067. Epub 2014 Dec 2.
The feasibility of a novel reverse-phase wet granulation process has been established previously highlighting several potential advantages over the conventional wet granulation process and making recommendations for further development of the approach. The feasibility study showed that in the reverse-phase process granule formation proceeds via a controlled breakage mechanism. Consequently, the aim of the present study was to investigate the effect of impeller speeds and binder liquid viscosity on the size distribution and intragranular porosity of granules using this novel process. Impeller tip speed was found to have different effects on the granules produced by a conventional as opposed to a reverse-phase granulation process. For the conventional process, an increase in impeller speed from 1.57 to 3.14 ms(-1) had minimal effect on granule size distribution. However, a further increase in impeller tip speed to 3.93 and 4.71 ms(-1) resulted in a decrease in intragranular porosity and a corresponding increase in mean granule size. In contrast when the reverse-phase process was used, an increase in impeller speed from 1.57 to 4.71 ms(-1) resulted in increased granule breakage and a decrease in the mean granule size. This was postulated to be due to the fact that the granulation process begins with fully saturated pores. Under these conditions further consolidation of granules at increased impeller tip speeds is limited and rebound or breakage occurs. Based on these results and analysis of the modified capillary number the conventional process appears to be driven by viscous forces whereas the reverse-phase process appears to be driven by capillary forces. Additionally, in the reverse-phase process a critical impeller speed, represented by the equilibrium between centrifugal and gravitational forces, appears to represent the point above which breakage of large wet agglomerates and mechanical dispersion of binder liquid take place. In contrast the conventional process appears to be difficult to control due to variations in granule consolidation, which depends upon experimental variables. Such variations meant increased impeller tip speed both decreased and increased granule size. The reverse-phase process appears to offer simple control over granule porosity and size through manipulation of the impeller speed and further evaluation of the approach is warranted.
先前已证实一种新型反相湿法制粒工艺的可行性，突出了其相较于传统湿法制粒工艺的若干潜在优势，并为该方法的进一步发展提出了建议。可行性研究表明，在反相工艺中，颗粒形成是通过可控的破碎机制进行的。因此，本研究的目的是使用这种新型工艺研究叶轮速度和黏合剂液体黏度对颗粒尺寸分布和颗粒内孔隙率的影响。发现叶轮叶尖速度对传统制粒工艺与反相制粒工艺所制得的颗粒有不同影响。对于传统工艺，叶轮速度从1.57增加到3.14 m·s⁻¹对颗粒尺寸分布影响极小。然而，叶轮叶尖速度进一步增加到3.93和4.71 m·s⁻¹导致颗粒内孔隙率降低，平均颗粒尺寸相应增加。相比之下，当使用反相工艺时，叶轮速度从1.57增加到4.71 m·s⁻¹导致颗粒破碎增加，平均颗粒尺寸减小。据推测，这是由于制粒过程始于完全饱和的孔隙。在这些条件下，叶轮叶尖速度增加时颗粒的进一步固结受到限制，会发生回弹或破碎。基于这些结果以及对修正毛细管数的分析，传统工艺似乎由黏性力驱动，而反相工艺似乎由毛细管力驱动。此外，在反相工艺中，由离心力和重力平衡表示的临界叶轮速度似乎代表了一个点，超过该点大的湿团聚体发生破碎且黏合剂液体发生机械分散。相比之下，传统工艺由于颗粒固结的变化而似乎难以控制，颗粒固结取决于实验变量。这种变化意味着叶轮叶尖速度增加时颗粒尺寸既减小又增大。反相工艺似乎通过控制叶轮速度对颗粒孔隙率和尺寸提供了简单的控制，因此有必要对该方法进行进一步评估。
