A novel four stage Cascade of Moving Baffle Oscillatory Crystallisers (CMBOC) is developed, characterised and implemented for continuous crystallisation of pharmaceuticals. The platform was fully automated with pressure controlled slurry transfer and process analytical tools (PAT) to support process monitoring and control. Model predictive control was used to achieve precise temperature control during operation of crystallisations. Mixing and flow characterisation for liquids and slurries was performed confirming near-ideal mixing performance for mean residence times in the range 20–90 min. Heat transfer characteristics were determined and shown to be well suited to the demands of cooling crystallisation processes. Heat transfer efficiency increased with increasing oscillatory Reynolds number (Re_o). This cascade is shown to provide the advantages of more uniform mixing and efficient heat transfer performance compared to a traditional cascade of stirred tank crystallisers. Continuous crystallisations of both alpha lactose monohydrate (ALM) and paracetamol (PCM) were carried out in which the target size, form, agglomeration and encrustation were controlled. For ALM, the products showed a narrow particle size distribution (PSD) with d_v50 = 65 ± 5 μm and a span of 1.4 ± 0.2, and achieved a yield of 70%. The continuous crystallisation of paracetamol in the CMBOC produced non-agglomerated product with d_v50 = 398 ± 20 μm with a span of 1.5 ± 0.2 and achieved an 85% yield. No fouling or encrustation in the vessels or transfer lines were observed during the processes. The flexible configuration and operation of the platform coupled with well characterised shear rate distribution, residence time distributions and heat transfer shows that this platform is well suited to a range of crystallisation modes including seeded, antisolvent, cooling or reactive processes, where careful control of crystal attributes is required.

中文翻译：

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级联移动折流振荡结晶器（CMBOC）的开发和表征

一种新型的四级级动挡板振荡结晶器（CMBOC）已开发，表征并实现了用于药物的连续结晶。该平台采用压力控制的浆料转移和过程分析工具（PAT）进行了完全自动化，以支持过程监控。模型预测控制用于在结晶过程中实现精确的温度控制。进行了液体和浆液的混合和流动表征，确认了在20–90分钟范围内的平均停留时间接近理想的混合性能。确定了传热特性，并显示出它非常适合冷却结晶过程的要求。传热效率随着振荡雷诺数（Re _o）。与传统的搅拌釜结晶器级联相比，该级联显示出提供更均匀混合和高效传热性能的优势。α-乳糖一水合物（ALM）和对乙酰氨基酚（PCM）均进行了连续结晶，其中目标尺寸，形式，团聚和结壳得到控制。对于ALM，产品显示出窄的粒度分布（PSD），d _v 50 = 65±5μm，跨度为1.4±0.2，并达到了70％的产率。扑热息痛在CMBOC中的连续结晶产生了具有d _v的非团聚产物50 = 398±20μm，跨度为1.5±0.2，实现了85％的产率。在此过程中，未观察到容器或输送管线有结垢或结垢。平台的灵活配置和操作以及良好的剪切速率分布，停留时间分布和传热特性表明，该平台非常适合一系列晶化模式，包括晶种，抗溶剂，冷却或反应过程，在此过程中，晶体应受到严格控制属性是必需的。