Polymorphic Control and Scale-Up Strategy for Antisolvent Crystallization Using Direct Nucleation Control,Crystal Growth & Design

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Polymorphic Control and Scale-Up Strategy for Antisolvent Crystallization Using Direct Nucleation Control
Crystal Growth & Design ( IF 3.2 ) Pub Date : 2020-03-02 , DOI: 10.1021/acs.cgd.0c00101
Iben Ostergaard ₁ , Botond Szilagyi ₂ , Heidi Lopez de Diego ₃ , Haiyan Qu ₁ , Zoltan K. Nagy ₂

Affiliation

In this work, a scale-up strategy based on the principles of direct design and quality-by-control (QbC) was applied and investigated using direct nucleation control (DNC). Process analytical technologies (PATs) were implemented for process monitoring and control. Antisolvent crystallization of indomethacin (IMC) was performed in a ternary solvent and antisolvent system. Mixture of acetone–methanol (66.5–33.5 wt %) was used as solvent and water as antisolvent since the mixed solvent system provides increased process yield and facilitates the suppression of the undesired acetone solvate. The effect of different process parameters, such as seed load, seed size, and initial concentration was investigated on process time, solid form and particle size distribution (PSD). The simplified solvent and antisolvent addition profiles obtained from the DNC were implemented directly in open-loop control to investigate reproducibility of the designed process. The open-loop operation was successfully scaled up by 1 order of magnitude, obtaining crystalline products with similar properties (solid form and PSD) as in the small-scale experiments. The results provide a proof-of-concept showing how the direct design approach can be applied in the rapid development of a robust crystallization process and efficient scale-up to yield the desired solid form with desired particulate properties (unimodal PSD and no agglomeration).

中文翻译：

使用直接成核控制进行反溶剂结晶的多态控制和放大策略

在这项工作中，应用了基于直接设计和控制质量（QbC）原理的放大策略，并使用直接成核控制（DNC）进行了研究。实施了过程分析技术（PAT）以进行过程监视和控制。在三元溶剂和反溶剂体系中进行消炎痛（IMC）的反溶剂结晶。丙酮-甲醇（66.5-33.5 wt％）的混合物用作溶剂，水用作反溶剂，因为混合溶剂系统可提高工艺收率并有助于抑制不希望的丙酮溶剂化物。研究了不同工艺参数（例如种子负载，种子大小和初始浓度）对处理时间，固体形式和粒度分布（PSD）的影响。从DNC获得的简化的溶剂和反溶剂添加曲线在开环控制中直接实现，以研究设计过程的可重复性。开环操作成功地按比例放大了一个数量级，获得了与小规模实验中具有相似性质（固体形式和PSD）的晶体产物。结果提供了概念证明，显示了如何将直接设计方法应用于快速开发的稳健结晶过程和有效放大工艺，以产生具有所需颗粒特性（单峰PSD和无团聚）的所需固体形式。获得具有与小规模实验相似的性质（固体形式和PSD）的结晶产物。结果提供了概念证明，显示了如何将直接设计方法应用于快速开发的稳健结晶过程和有效放大工艺，以产生具有所需颗粒特性（单峰PSD和无团聚）的所需固体形式。获得具有与小规模实验相似的性质（固体形式和PSD）的结晶产物。结果提供了概念证明，显示了如何将直接设计方法应用于快速开发的稳健结晶过程和有效放大工艺，以产生具有所需颗粒特性（单峰PSD和无团聚）的所需固体形式。

更新日期：2020-04-23

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