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Polymorphic Control and Scale-up Strategy for Crystallization from a Ternary Antisolvent System by Supersaturation Control
Crystal Growth & Design ( IF 3.2 ) Pub Date : 2020-01-10 , DOI: 10.1021/acs.cgd.9b01623 Iben Ostergaard 1 , Botond Szilagyi 2 , Zoltan K. Nagy 2 , Heidi Lopez de Diego 3 , Haiyan Qu 1
Crystal Growth & Design ( IF 3.2 ) Pub Date : 2020-01-10 , DOI: 10.1021/acs.cgd.9b01623 Iben Ostergaard 1 , Botond Szilagyi 2 , Zoltan K. Nagy 2 , Heidi Lopez de Diego 3 , Haiyan Qu 1
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Antisolvent crystallization of indomethacin (IMC) was investigated in this work by using an acetone–methanol (66.5–33.5 wt %) mixture as solvent and water as antisolvent. Selecting the binary mixture as the solvent led to an increased yield of the batch process, as the solubility of IMC is higher in the mixed solvents. Adding methanol to the solvent system mitigated the nucleation of the acetone solvate, which is dominating in the acetone–water system. Process analytical technologies were implemented to ensure that the desired polymorph was present throughout the process. Supersaturation control (SSC) was applied as a closed-loop feedback control strategy, to achieve a rapid direct design of the crystallization process using the principles of quality by control. The antisolvent flow-rate profiles, obtained by the SSC, were implemented in open loop and used for scaling up the process by 1 order of magnitude. The results show how feedback control of crystallization from a ternary solvent mixture increases productivity and simultaneously ensures suppression of nucleation to obtain the desired particle size distribution and polymorph. The direct design approach can be applied in the design and development of crystallization processes to yield the chosen solid phase of IMC when scaling from small to large scale.
中文翻译：
三元反溶剂系统过饱和控制结晶的多态控制和放大策略
在这项工作中，使用丙酮-甲醇（66.5-33.5 wt％）混合物作为溶剂，用水作为反溶剂，研究了吲哚美辛（IMC）的反溶剂结晶。选择二元混合物作为溶剂可提高分批工艺的产率，因为IMC在混合溶剂中的溶解度更高。在溶剂系统中添加甲醇可减轻丙酮溶剂化物的形核，该溶剂化物在丙酮-水系统中占主导地位。实施过程分析技术以确保在整个过程中都存在所需的多晶型物。过饱和控制（SSC）被用作闭环反馈控制策略，以通过控制的质量原则实现结晶过程的快速直接设计。由SSC获得的反溶剂流速分布图 它们是在开环中实现的，用于按比例放大1个数量级的过程。结果表明，从三元溶剂混合物中结晶的反馈控制如何提高生产率并同时确保抑制成核以获得所需的粒度分布和多晶型物。直接设计方法可用于结晶过程的设计和开发，以在从小规模到大规模规模生产时产生所选的IMC固相。
更新日期：2020-01-10
中文翻译：
三元反溶剂系统过饱和控制结晶的多态控制和放大策略
在这项工作中，使用丙酮-甲醇（66.5-33.5 wt％）混合物作为溶剂，用水作为反溶剂，研究了吲哚美辛（IMC）的反溶剂结晶。选择二元混合物作为溶剂可提高分批工艺的产率，因为IMC在混合溶剂中的溶解度更高。在溶剂系统中添加甲醇可减轻丙酮溶剂化物的形核，该溶剂化物在丙酮-水系统中占主导地位。实施过程分析技术以确保在整个过程中都存在所需的多晶型物。过饱和控制（SSC）被用作闭环反馈控制策略，以通过控制的质量原则实现结晶过程的快速直接设计。由SSC获得的反溶剂流速分布图 它们是在开环中实现的，用于按比例放大1个数量级的过程。结果表明，从三元溶剂混合物中结晶的反馈控制如何提高生产率并同时确保抑制成核以获得所需的粒度分布和多晶型物。直接设计方法可用于结晶过程的设计和开发，以在从小规模到大规模规模生产时产生所选的IMC固相。
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