Fast Continuous Non-Seeded Cooling Crystallization of Glycine in Slug Flow: Pure α-Form Crystals with Narrow Size Distribution

Abstract

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. 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. 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. 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.