a Krka, d.d., Novo mesto , Šmarješka cesta 6 , Novo mesto , Slovenia.
b Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged , Eötvös u. 6 , Szeged , Hungary.
Drug Dev Ind Pharm. 2018 Nov;44(11):1770-1782. doi: 10.1080/03639045.2018.1496447. Epub 2018 Sep 7.
Knowledge of the effects of high-shear granulation process parameters and scale-up on the properties of the produced granules is essential for formulators who face challenges regarding poor flow and compaction during development of modified release tablets based on high-molecular weight hypromellose (hydroxypropylmethylcellulose (HPMC)) polymers. Almost none of the existing studies deal with realistic industrial formulation.
The aim was to investigate the effects of scale-up and critical process parameters (CPPs) of high-shear granulation on the quality attributes of the granules, particularly in terms of the flow and compaction, using a realistic industrial formulation based on HPMC K100M polymer.
The flow properties were determined using flow time, Carr index, tablet mass, and crushing strength variations. The compaction properties were quantified using the 'out-of-die' Heckel and modified Walker models, as well as the tensile strength profile and elastic recovery. High-shear granulation was performed at different scales: 4 L, 300 L, and 600 L.
The scale itself had larger effects on the granule properties than the CPPs, which demonstrated high robustness of formulation on the individual scale level. Nevertheless, to achieve the desired flow and compaction, the values of the CPPs need to be precisely selected to fine-tune the process conditions. The best flow was achieved at high volumes of water addition, where larger and more spherical granules were obtained. The CPPs showed negligible influence on the compaction with no practical implications, however, the volume of water addition volume was identified as having the largest effects on compaction.
对于那些在开发基于高分子量羟丙甲纤维素（羟丙甲纤维素（HPMC））聚合物的控释片剂时面临流动性和可压缩性差的挑战的制剂师来说，了解高剪切制粒工艺参数和放大对所生产颗粒性能的影响至关重要。几乎没有现有的研究涉及实际的工业配方。
本研究旨在使用基于 HPMC K100M 聚合物的真实工业配方，研究高剪切制粒的放大和关键工艺参数（CPP）对颗粒质量属性的影响，特别是在流动性和可压缩性方面。
使用流动时间、卡尔指数、片剂质量和破碎强度变化来确定流动性能。使用“出模” Heckel 和改进的 Walker 模型以及拉伸强度曲线和弹性恢复来量化压缩性能。在不同规模下进行高剪切制粒：4 L、300 L 和 600 L。
规模本身对颗粒性质的影响大于 CPP，这表明配方在各个规模水平上具有较高的稳健性。然而，为了达到所需的流动性和可压缩性，需要精确选择 CPP 值来微调工艺条件。在添加大量水的情况下可获得最佳的流动性，从而获得更大且更球形的颗粒。CPP 对压缩的影响可忽略不计，没有实际意义，但是，添加水的体积被确定为对压缩有最大的影响。
