Van Snick B, Holman J, Cunningham C, Kumar A, Vercruysse J, De Beer T, Remon J P, Vervaet C
Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium.
GEA APC Pharma Solids, Eastleigh, United Kingdom.
Int J Pharm. 2017 Mar 15;519(1-2):390-407. doi: 10.1016/j.ijpharm.2017.01.010. Epub 2017 Jan 6.
This study presents a framework for process and product development on a continuous direct compression manufacturing platform. A challenging sustained release formulation with high content of a poorly flowing low density drug was selected. Two HPMC grades were evaluated as matrix former: standard Methocel CR and directly compressible Methocel DC2. The feeding behavior of each formulation component was investigated by deriving feed factor profiles. The maximum feed factor was used to estimate the drive command and depended strongly upon the density of the material. Furthermore, the shape of the feed factor profile allowed definition of a customized refill regime for each material. Inline NIRs was used to estimate the residence time distribution (RTD) in the mixer and monitor blend uniformity. Tablet content and weight variability were determined as additional measures of mixing performance. For Methocel CR, the best axial mixing (i.e. feeder fluctuation dampening) was achieved when an impeller with high number of radial mixing blades operated at low speed. However, the variability in tablet weight and content uniformity deteriorated under this condition. One can therefore conclude that balancing axial mixing with tablet quality is critical for Methocel CR. However, reformulating with the direct compressible Methocel DC2 as matrix former improved tablet quality vastly. Furthermore, both process and product were significantly more robust to changes in process and design variables. This observation underpins the importance of flowability during continuous blending and die-filling. At the compaction stage, blends with Methocel CR showed better tabletability driven by a higher compressibility as the smaller CR particles have a higher bonding area. However, tablets of similar strength were achieved using Methocel DC2 by targeting equal porosity. Compaction pressure impacted tablet properties and dissolution. Hence controlling thickness during continuous manufacturing of sustained release tablets was crucial to ensure reproducible dissolution.
本研究提出了一个在连续直接压缩制造平台上进行工艺和产品开发的框架。选择了一种具有挑战性的高含量低流动性低密度药物的缓释制剂。评估了两种羟丙甲纤维素等级作为基质形成剂：标准的美多秀CR和可直接压缩的美多秀DC2。通过推导进料因子曲线研究了每种制剂成分的进料行为。最大进料因子用于估计驱动指令，并且强烈依赖于物料的密度。此外，进料因子曲线的形状允许为每种物料定义定制的再填充方案。在线近红外光谱用于估计混合器中的停留时间分布（RTD）并监测混合均匀性。测定片剂含量和重量变异性作为混合性能的额外指标。对于美多秀CR，当具有大量径向混合叶片的叶轮低速运行时，可实现最佳的轴向混合（即进料器波动抑制）。然而，在此条件下片剂重量和含量均匀性的变异性恶化。因此可以得出结论，对于美多秀CR，平衡轴向混合与片剂质量至关重要。然而，改用可直接压缩的美多秀DC2作为基质形成剂极大地改善了片剂质量。此外，工艺和产品对工艺和设计变量的变化都具有显著更高的稳健性。这一观察结果强调了连续混合和模腔填充过程中流动性的重要性。在压片阶段，含有美多秀CR的混合物由于较小的CR颗粒具有更高的结合面积，由更高的压缩性驱动，表现出更好的可压性。然而，通过设定相同的孔隙率，使用美多秀DC2也可获得强度相似的片剂。压片压力会影响片剂性质和溶出度。因此，在连续制造缓释片剂过程中控制厚度对于确保可重复的溶出度至关重要。
