Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13/2, 8010 Graz, Austria.
Int J Pharm. 2013 Oct 15;455(1-2):159-68. doi: 10.1016/j.ijpharm.2013.07.044. Epub 2013 Jul 31.
Implementation of continuous manufacturing in the pharmaceutical industry requires tight process control. This study focuses on a PAT strategy for hot melt extrusion of vegetable calcium stearate (CaSt) as matrix carrier and paracetamol as active pharmaceutical ingredient (API). The extrusion was monitored using in-line near-infrared (NIR) spectroscopy. A NIR probe was located in the section between the extrusion screws and the die, using a novel design of the die channel. A chemometric model was developed based on premixes at defined concentrations and was implemented in SIPAT for real time API concentration monitoring. Subsequently, step experiments were performed for different API concentrations, screw speeds and screw designs. The predicted API concentration was in good agreement with the pre-set concentrations. The transition from one API plateau to another was a smooth curve due to the mixing behaviour of the extruder. The accuracy of the model was confirmed via offline HPLC analysis. The screw design was determined as the main influential factor on content uniformity (CU). Additionally the influence of multiple feeders had a significant impact on CU. The results demonstrate that in-line NIR measurements is a powerful tool for process development (e.g., mixing characterization), monitoring and further control strategies.
在制药行业实施连续制造需要严格的过程控制。本研究聚焦于热熔挤出蔬菜硬脂酸钙（CaSt）作为基质载体和扑热息痛（API）的过程分析技术（PAT）策略。使用在线近红外（NIR）光谱法监测挤出过程。NIR 探头位于挤出螺杆和模具之间的部分，采用模具通道的新颖设计。基于预混物在规定浓度下开发了化学计量学模型，并在 SIPAT 中实现了实时 API 浓度监测。随后，针对不同的 API 浓度、螺杆速度和螺杆设计进行了阶跃实验。预测的 API 浓度与预设浓度非常吻合。由于挤出机的混合行为，从一个 API 平台到另一个平台的过渡是一条平滑的曲线。通过离线 HPLC 分析证实了模型的准确性。螺杆设计被确定为含量均匀度（CU）的主要影响因素。此外，多进料器的影响对 CU 有显著影响。结果表明，在线 NIR 测量是用于过程开发（例如混合特性）、监测和进一步控制策略的有力工具。
