Bouwman A M, Henstra M J, Westerman D, Chung J T, Zhang Z, Ingram A, Seville J P K, Frijlink H W
Department of Pharmaceutical Technology & Biopharmacy, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Int J Pharm. 2005 Feb 16;290(1-2):129-36. doi: 10.1016/j.ijpharm.2004.11.024. Epub 2005 Jan 12.
The structure of granules changes during the high shear granulation process. The purpose of this research was to investigate the effect of the amount of binder liquid on the structure of the granules and the structural changes which occur during the granulation process, using microcrystalline cellulose (MCC) and water as the model system. The structure is the result of the granulation mechanism; therefore, conclusions can be drawn about the latter by studying the former. X-ray microtomography and scanning electron microscopy (SEM) were applied in order to visualise the densification process of granules, which were first freeze dried in order to preserve their structure. Variations in their porosity were quantified by applying image analysis to the tomography results. In order to link the granule mechanical properties to their structural differences, a micromanipulation technique was used to measure granule resistance to deformation. MCC granules granulated with 100% (w/w) water showed increased densification with time, as expected; detailed examination showed that densification is more pronounced in the core of the granule; whereas the outer part remained more porous. Increased densification reduces deformability, so that granules become more resistant to breakage. The lower deformability of the densified granules in the final stages of granulation might result in establishment of equilibrium between attrition and growth, without substantial gross breakage. On the other hand, when more water was used (125%, w/w), densification was hardly observed; the porosity of the granule core was still high even after prolonged granulation times. This may be explained by the fact that higher water content increases the ease of deformation of granules. This increased deformability led to significant granule breakage even during the final phases of the granulation process. Therefore, for these granules a final equilibrium between breakage and coalescence might be established. This also explains why more granules produced with 125% granulation liquid were composed of fragments of irregular shape. Our results establish the link between the granulation behaviour of MCC in the latter stages and the material structure of these granules, which is determined by their liquid content. The process conditions (amount of liquid) to be chosen depend largely on the final purpose for which the granular material is produced.
在高剪切制粒过程中，颗粒的结构会发生变化。本研究的目的是使用微晶纤维素（MCC）和水作为模型体系，研究黏合剂液体用量对颗粒结构以及制粒过程中发生的结构变化的影响。结构是制粒机制的结果；因此，通过研究前者可以得出关于后者的结论。应用X射线显微断层扫描和扫描电子显微镜（SEM）来观察颗粒的致密化过程，颗粒首先进行冷冻干燥以保留其结构。通过对断层扫描结果应用图像分析来量化其孔隙率的变化。为了将颗粒的力学性能与其结构差异联系起来，使用微操纵技术测量颗粒的抗变形能力。用100%（w/w）水制粒的MCC颗粒随时间显示出致密化增加，正如预期的那样；详细检查表明，致密化在颗粒核心更为明显；而外部部分仍然孔隙较多。致密化增加会降低可变形性，从而使颗粒更耐破碎。在制粒后期致密化颗粒的较低可变形性可能导致磨损和生长之间建立平衡，而不会出现大量的总体破碎。另一方面，当使用更多的水（125%，w/w）时，几乎观察不到致密化；即使经过长时间的制粒，颗粒核心的孔隙率仍然很高。这可以用较高的含水量增加颗粒变形的容易程度这一事实来解释。这种增加的可变形性甚至在制粒过程的最后阶段也导致了显著的颗粒破碎。因此，对于这些颗粒，可能会在破碎和聚结之间建立最终平衡。这也解释了为什么用125%制粒液生产的更多颗粒是由不规则形状的碎片组成。我们的结果建立了MCC在后期的制粒行为与这些颗粒的材料结构之间的联系，而这种结构由它们的液体含量决定。要选择的工艺条件（液体用量）在很大程度上取决于生产颗粒材料的最终目的。
