Abstract Continuous crystallization of active pharmaceutical ingredients is of prime significance. A continuous mixed suspension mixed product removal (MSMPR)-tubular crystallizer geometry is designed and optimized to produce the metastable α-form crystals of L-glutamic acid with uniform mean size of 130 µm. The MSMPR is used to produce well-tuned seed crystals that undergo further growth in a series of tubular crystallizers. The effects of the initial supersaturation, stirring speed, nucleation temperature and residence time were optimized in the MSMPR crystallizer to tune the supply of continuous seeds by using the principal component analysis and in-situ particle tracking measurement. The continuous seeds of the desired metastable polymorphic form with specific size ranging from 5.0 to 15.0 µm and number density ranging from 500 to 1500 counts, were transferred to a series of three coiled tubular crystallizers for further growth. In addition, the cooling strategy in the tubular crystallizers was utilized to further optimize the quality of the final crystal product. The crystal size distribution (CSD) in the MSMPR-tubular crystallizer system was compared with a single MSMPR with the same residence time and found to be superior. Finally, a potential scale up strategy of the MSMPR-tubular crystallizer system was proposed for further study.

中文翻译：

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在 MSMPR-管式结晶器系统中连续结晶 α-型 L-谷氨酸

摘要 活性药物成分的连续结晶具有重要意义。设计并优化了连续混合悬浮混合产物去除 (MSMPR)-管状结晶器几何形状，以生产平均尺寸为 130 µm 的 L-谷氨酸亚稳态 α 型晶体。MSMPR 用于生产经过良好调节的晶种，这些晶种在一系列管状结晶器中进一步生长。在 MSMPR 结晶器中优化初始过饱和度、搅拌速度、成核温度和停留时间的影响，以通过使用主成分分析和原位颗粒跟踪测量来调整连续晶种的供应。所需亚稳态多晶型的连续种子，特定尺寸范围为 5.0 至 15.0 µm，数密度范围为 500 至 1500 个计数，被转移到一系列三个盘管式结晶器中以进一步生长。此外，管式结晶器中的冷却策略被用来进一步优化最终晶体产品的质量。将 MSMPR 管式结晶器系统中的晶体尺寸分布 (CSD) 与具有相同停留时间的单个 MSMPR 进行比较，发现其更优。最后，提出了 MSMPR-管状结晶器系统的潜在放大策略以供进一步研究。将 MSMPR 管式结晶器系统中的晶体尺寸分布 (CSD) 与具有相同停留时间的单个 MSMPR 进行比较，发现其更优。最后，提出了 MSMPR-管状结晶器系统的潜在放大策略以供进一步研究。将 MSMPR 管式结晶器系统中的晶体尺寸分布 (CSD) 与具有相同停留时间的单个 MSMPR 进行比较，发现其更优。最后，提出了 MSMPR-管状结晶器系统的潜在放大策略以供进一步研究。