Department of Pharmaceutics, Rutgers University, Piscataway, NJ 08854, USA.
Department of Chemical and Biochemical Engineering, Rutgers University, Piscataway, NJ 08854, USA; Genentech, Inc., South San Francisco, CA 94080, USA.
Int J Pharm. 2019 Feb 10;556:349-362. doi: 10.1016/j.ijpharm.2018.12.009. Epub 2018 Dec 12.
Nowadays twin-screw granulation has been emerging as an attractive continuous wet granulation technique. This study was geared towards better process design and understanding with emphasis on bridging the knowledge gap between input and output variables by employing sequential experimentation strategy. A low-dose formulation for granulation experiments contained anhydrous caffeine as the model drug. In the first phase of parameter screening, D-optimal design and stepwise regression were leveraged to develop interaction models following the examination of various quantitative and qualitative factors of potential importance. To maximize the design space dictated by predefined quality target values, several variables were fixed at optimum levels: 700 rpm screw speed, 60° kneading element staggering angle, 5 kneading elements and distributive feed screw in the screw configuration. In the second phase of characterization, response surface design was utilized to investigate the dependence of critical quality attributes of granules and tablets on selected critical process parameters (L/S ratio, throughput and barrel temperature). The results indicated that the influence of throughput and barrel temperature was relatively inferior to L/S ratio. Higher degree of liquid saturation led to granules with narrower size distribution, smaller porosity and enhanced flowability and tablets with declining tensile strength yet slackened drug release.
如今，双螺杆造粒已成为一种颇具吸引力的连续湿法造粒技术。本研究旨在通过采用序贯实验策略，更好地进行工艺设计和理解，重点是弥合输入和输出变量之间的知识差距。用于造粒实验的低剂量配方含有无水咖啡因作为模型药物。在参数筛选的第一阶段，利用 D-最优设计和逐步回归，在检查各种潜在重要的定量和定性因素后，开发出了相互作用模型。为了最大限度地利用根据预设质量目标值规定的设计空间，将几个变量固定在最佳水平：螺杆速度 700rpm、捏合元件错开角度 60°、5 个捏合元件和螺杆配置中的分配进料螺杆。在特征描述的第二阶段，利用响应面设计研究了关键工艺参数（固液比、流量和筒体温）对颗粒和片剂关键质量属性的影响。结果表明，流量和筒体温的影响相对低于固液比。更高的液体饱和度导致颗粒具有更窄的粒径分布、更小的孔隙率和增强的流动性，以及片剂的拉伸强度下降但药物释放减缓。
