Continuous In Situ Seed Generation through the Integration of a Mixed Suspension Mixed Product Removal and an Oscillatory Baffled Crystallizer for the Control of Crystal Size Distribution and Polymorphic Form,Crystal Growth & Design

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Continuous In Situ Seed Generation through the Integration of a Mixed Suspension Mixed Product Removal and an Oscillatory Baffled Crystallizer for the Control of Crystal Size Distribution and Polymorphic Form
Crystal Growth & Design ( IF 3.2 ) Pub Date : 2021-11-10 , DOI: 10.1021/acs.cgd.1c00301
Wei-Lee Wu ₁ , Joseph A. Oliva ₁ , Shivani Kshirsagar _{1,

2} , Christopher L. Burcham ₃ , Zoltan K. Nagy ₁

Affiliation

Fouling, encrustation, and lack of polymorphic form control are some of the major drawbacks of continuous oscillatory baffled crystallizers (COBCs), which can lead to clogging, undesired crystal form generation, and process failure. To counter these drawbacks, seeding with crystals is a methodology to not only control nucleation mechanism and crystal size distribution (CSD) but also provide polymorphic form control. Consistent manual preparation of seeds for continuous crystallization is labor-intensive and often economically infeasible. Furthermore, any fluctuations of seed quality can impact the startup dynamics. In this work, a proof-of-concept and the benefits of continuous in situ seed generation was demonstrated with an integration of a mixed suspension mixed product removal (MSMPR) crystallizer with a COBC via a continuous combined cooling antisolvent crystallization (CCAC). First, a CCAC solubility design space of metastable (form II) and stable forms (form I) of ortho-aminobenzoic acid was developed to identify operating regimes for selective polymorphic form generation. Second, the in situ form I seed generation experiments, with the COBC, prolonged steady-state generation of the crystal product for more than eight residence times. The crystal product generated from the combined system with segmented cooling had a higher mean size and narrower size distribution when compared to the product obtained from a single-stage MSMPR experiment. Polymorphic control coupled with continuous seed generation in the combined system generated a uniform crystal product with no seed wash out occurring. Lastly, the importance of the method of slurry transport for the combined system was highlighted in experiments utilizing mechanical pump transfer compared to gravimetric transfer. Overall, these proof-of-concept experiments demonstrated the feasibility and benefits of using the integrated MSMPR–COBC crystallization system, utilizing the MSMPR crystallizer for continuous in situ seed generation providing for the robust operation of the COBCs.

中文翻译：

通过混合悬浮混合产品去除和振荡挡板结晶器的集成进行连续原位种子生成，以控制晶体尺寸分布和多晶型

结垢、结壳和缺乏多晶型控制是连续振荡挡板结晶器 (COBC) 的一些主要缺点，这会导致堵塞、不希望的晶型生成和工艺失败。为了克服这些缺点，用晶体接种是一种方法，不仅可以控制成核机制和晶体尺寸分布 (CSD)，还可以提供多晶型控制。为连续结晶而一致地手动制备种子是劳动密集型的并且通常在经济上不可行。此外，种子质量的任何波动都会影响启动动态。在这项工作中，概念验证和连续原位的好处通过连续组合冷却抗溶剂结晶 (CCAC) 将混合悬浮混合产物去除 (MSMPR) 结晶器与 COBC 集成在一起，证明了种子生成。首先，开发了邻氨基苯甲酸亚稳态（II型）和稳定型（I型）的CCAC溶解度设计空间，以确定选择性多晶型生成的操作方式。二、就地使用 COBC 的 I 型晶种生成实验延长了晶体产物的稳态生成时间超过八次。与从单级 MSMPR 实验获得的产品相比，由具有分段冷却的组合系统产生的晶体产品具有更高的平均尺寸和更窄的尺寸分布。多晶型控制与组合系统中的连续种子生成相结合，生成了均匀的晶体产品，不会发生种子洗出。最后，与重力传输相比，在使用机械泵传输的实验中强调了组合系统泥浆传输方法的重要性。总的来说，这些概念验证实验证明了使用集成的 MSMPR-COBC 结晶系统的可行性和好处，原位种子生成为 COBC 的稳健运行提供了条件。

更新日期：2021-12-01

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