Innovations in the continuous crystallization field are required for the pharmaceutical industry to go through the paradigm shift from batch to continuous processing. To do so, different risks associated with the continuous crystallization have to be identified and discussed. In this work, a continuous antisolvent crystallization of the model compound indomethacin (IMC) from a ternary solvent system in a mixed-suspension-mixed-product-removal (MSMPR) to produce the desired polymorphic γ-form is evaluated, and potential risks for process failure are identified. One of the main risks identified with the continuous crystallization is gaining a balance between the inlet and outlet flows. Two novel and different level controls are proposed in this work to overcome this risk, an ultrasonic sensor and image analysis based on a video recording of the level. These two methods demonstrate improved process robustness upon implementation. Additionally, different process parameters were investigated and showed that the seed load has a significant effect on maintaining the desired polymorph and avoiding process failure. To the best of our knowledge, this is the first study on continuous crystallization of IMC for the polymorphic control of γ-IMC.

中文翻译：

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多态控制的连续混合悬浮混合产品去除反溶剂结晶过程的基于风险的操作

制药行业需要不断结晶领域的创新，以实现从批处理到连续处理的范式转变。为此，必须确定和讨论与连续结晶有关的不同风险。在这项工作中，评估了模型化合物吲哚美辛（IMC）在混合悬浮液混合产物去除（MSMPR）中从三元溶剂系统中连续反溶剂结晶以生成所需多晶型γ形式的可能性，并评估了潜在的风险识别过程失败。连续结晶确定的主要风险之一是在入口和出口流量之间取得平衡。在这项工作中，提出了两种新颖且不同级别的控件来克服这种风险，超声波传感器和基于水平视频记录的图像分析。这两种方法在实现时都显示出改进的过程鲁棒性。此外，研究了不同的工艺参数，结果表明，种子负载对维持所需的多晶型物和避免工艺失败具有重大影响。据我们所知，这是对IMC连续结晶用于γ-IMC多态控制的首次研究。