Pal Sayan, Pankajakshan Arun, Besenhard Maximilian O, Snead Nicholas, Almeida Juan, Abukhamees Shorooq, Craig Duncan, Galvanin Federico, Gavriilidis Asterios, Mazzei Luca
Department of Chemical Engineering, University College London, Torrington Place, London WC1E 7JE, U.K.
Perceptive Engineering, Applied Materials, Vanguard House, Keckwick Lane, Sci Tech Daresbury, Cheshire WA4 4AB, U.K.
Org Process Res Dev. 2024 Jul 9;28(7):2755-2764. doi: 10.1021/acs.oprd.4c00110. eCollection 2024 Jul 19.
The fourth industrial revolution is gaining momentum in the pharmaceutical industry. However, particulate processes and suspension handling remain big challenges for automation and the implementation of real-time particle size analysis. Moreover, the development of antisolvent crystallization processes is often limited by the associated time-intensive experimental screenings. This work demonstrates a fully automated modular crystallization platform that overcomes these bottlenecks. The system combines automated crystallization, sample preparation, and immediate crystal size analysis via online laser diffraction (LD) and provides a technology for rapidly screening crystallization process parameters and crystallizer design spaces with minimal experimental effort. During the LD measurements, to avoid multiple scattering events, crystal suspension samples are diluted automatically. Multiple software tools, i.e., LabVIEW, Python, and PharmaMV, and logic algorithms are integrated in the platform to facilitate automated control of all the sensors and equipment, enabling fully automated operation. A customized graphical user interface is provided to operate the crystallization platform automatically and to visualize the measured crystal size and the crystal size distribution of the suspension. Antisolvent crystallization of ibuprofen, with ethanol as solvent and water with Soluplus (an additive) as antisolvent, is used as a case study. The platform is demonstrated for antisolvent crystallization of small ibuprofen crystals in a confined impinging jet crystallizer, performing automated preplanned user-defined experiments with online LD analysis.
第四次工业革命正在制药行业蓬勃发展。然而，颗粒过程和悬浮液处理仍然是自动化和实时粒度分析实施面临的重大挑战。此外，抗溶剂结晶过程的开发往往受到相关耗时实验筛选的限制。这项工作展示了一个克服这些瓶颈的全自动模块化结晶平台。该系统结合了自动结晶、样品制备以及通过在线激光衍射（LD）进行即时晶体尺寸分析，并提供了一种以最少的实验工作量快速筛选结晶工艺参数和结晶器设计空间的技术。在LD测量过程中，为避免多次散射事件，晶体悬浮液样品会自动稀释。多个软件工具，即LabVIEW、Python和PharmaMV，以及逻辑算法集成在该平台中，以促进对所有传感器和设备的自动控制，实现完全自动化操作。提供了一个定制的图形用户界面来自动操作结晶平台，并可视化测量的晶体尺寸和悬浮液的晶体尺寸分布。以乙醇为溶剂、水与Soluplus（一种添加剂）为抗溶剂的布洛芬抗溶剂结晶作为案例研究。该平台在受限撞击流结晶器中对小尺寸布洛芬晶体的抗溶剂结晶进行了演示，通过在线LD分析执行自动预先规划的用户定义实验。
