Purpose

Glycine has been widely used as pharmaceutical excipients and synthesis reagents, and commercial glycine has a significant amount of aggregation and wide particle size distribution. A simple but reproducible process for generating uniform glycine crystals is always desired for both product quality and process efficiency purposes.

Methods

Continuous cooling crystallization of glycine has been carried out in air-liquid slug flow in millimeter ID tubing, starting from solution without using seeds. Slugs were formed by combining air and liquid streams, then went through the crash cooling zone of varying lengths (tubing length in contact with ice bags). The operational boundaries of crash cooling times were evaluated: natural cooling (lower bound, no crash cooling), maximum cooling time for pure α-form without aggregation (upper bound), and beyond upper bound.

Results

Non-aggregating pure α-form glycine crystals were continuously generated within ~ 10 min, feasible from multiple conditions (combinations of crashing cooling time and starting concentration). When crash cooling time further increases (while maintaining the starting concentration), crystal aggregations and/or γ-form crystals could appear. Reducing starting concentration can allow longer crash cooling time without widening product crystal size distribution or reducing crystalline form purity. At proper conditions, even natural cooling in slugs can nucleate and grow non-aggregated pure α-form crystals. All cooling conditions carried out in slug flow generally minimize needle-shaped crystals compared with corresponding batches.

Conclusion

Glycine crystals of α-form and narrow size distribution can be continuously generated within 10 min from cooling crystallization in millimeter-sized slug flow, without using external seeds nor adding solvent/additives. And, the operational boundaries of crash cooling time (at proper starting concentrations) for pure α-form non-aggregating product crystals are identified.

中文翻译：

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团状流中甘氨酸的快速连续非播种冷却结晶：具有窄尺寸分布的纯α形晶体

目的

甘氨酸已被广泛用作药物赋形剂和合成试剂，而商业甘氨酸具有大量聚集和宽粒度分布。出于产品质量和过程效率的目的，总是需要一种简单但可再现的方法来产生均匀的甘氨酸晶体。

方法

甘氨酸的连续冷却结晶是在毫米内径的气液塞流中进行的，从不使用种子的溶液开始。通过合并空气和液体流形成团块，然后通过不同长度（与冰袋接触的管道长度）的碰撞冷却区。评估了碰撞冷却时间的操作边界：自然冷却（下限，无碰撞冷却），无聚集的纯α形式的最大冷却时间（上限），以及超过上限。

结果

在约10分钟内可连续生成非聚集的纯α型甘氨酸晶体，这在多种条件下均可实现（冷却时间骤升和起始浓度的组合）。当碰撞冷却时间进一步增加（同时保持起始浓度）时，会出现晶体聚集和/或γ形晶体。降低起始浓度可允许更长的碰撞冷却时间，而不会扩大产品的晶体尺寸分布或降低晶型纯度。在适当的条件下，即使团状棒自然冷却，也可能成核并生长出非聚集的纯α型晶体。与相应批次相比，以团状流方式进行的所有冷却条件通常会使针状晶体最小化。

结论

在不使用外部晶种或不添加溶剂/添加剂的情况下，以毫米大小的团状流冷却结晶后，可以在10分钟内连续生成α型甘氨酸晶体和窄尺寸分布的甘氨酸晶体。并且，确定了纯α型非聚集产物晶体的碰撞冷却时间（在适当的起始浓度下）的操作边界。