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.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Myerson AS. Handbook of industrial crystallization. 2nd ed. Woburn, MA: Butterworth-Heinemann; 2002.
Mullin JW. Crystallization. 4th ed. Oxford: Butterworth-Heinemann; 2001.
Tung H-H, Paul EL, Midler M, McCauley JA. Crystallization of pharmaceuticals: an industrial perspective. Hoboken, NJ: Wiley; 2009.
Lewis EA, Seckler MM, Kramer H, van Rosmalen G. Industrial crystallization: fundamentals and applications. Cambridge: Cambridge University Press; 2015.
Yu LX. Pharmaceutical quality by design: product and process development, understanding, and control. Pharm Res. 2008;25:781–91.
Zhang D, Xu S, Du S, Wang J, Gong J. Progress of pharmaceutical continuous crystallization. Engineering. 2017;3:354–64.
Rimez B, Debuysschère R, Conté J, Lecomte-Norrant E, Gourdon C, Cognet P, et al. Continuous-flow tubular crystallization to discriminate between two competing crystal polymorphs. 1. Cooling crystallization. Cryst Growth Des. 2018;18:6431–9.
Narayan ST. Industrial crystallization: process simulation analysis and design. Boston, MA: Springer; 1995.
Wang H, Mustaffar A, Phan AN, Zivkovic V, Reay D, Law R, et al. A review of process intensification applied to solids handling. Chem Eng Process Process Intensif. 2017;118:78–107.
Nagy ZK, Fujiwara M, Braatz RD. Monitoring and advanced control of crystallization processes. In: Lee AY, Myerson AS, Erdemir D, editors. Handb. Ind. Cryst. 3rd ed. Cambridge: Cambridge University Press; 2019.
Lovette MA, Browning AR, Griffin DW, Sizemore JP, Snyder RC, Doherty MF. Crystal shape engineering. Ind Eng Chem Res. 2008;47:9812–33.
Brown CJ, McGlone T, Yerdelen S, Srirambhatla V, Mabbott F, Gurung R, et al. Enabling precision manufacturing of active pharmaceutical ingredients: workflow for seeded cooling continuous crystallisations. Mol Syst Des Eng. 2018;3:518–49.
Wang T, Lu H, Wang J, Xiao Y, Zhou Y, Bao Y, et al. Recent progress of continuous crystallization. J Ind Eng Chem. 2017;54:14–29.
Jiang M, Braatz RD. Designs of continuous-flow pharmaceutical crystallizers: developments and practice. CrystEngComm. 2019;21:3534–51.
Lawton S, Steele G, Shering P, Zhao L, Laird I, Ni XW. Continuous crystallization of pharmaceuticals using a continuous oscillatory baffled crystallizer. Org Process Res Dev. 2009;13:1357–63.
Power G, Hou G, Kamaraju VK, Morris G, Zhao Y, Glennon B. Design and optimization of a multistage continuous cooling mixed suspension, mixed product removal crystallizer. Chem Eng Sci. 2015;133:125–39.
Li J, Trout BL, Myerson AS. Multistage continuous mixed-suspension, mixed-product removal (MSMPR) crystallization with solids recycle. Org Process Res Dev. 2016;20:510–6.
Briggs NEB, Schacht U, Raval V, McGlone T, Sefcik J, Florence AJ. Seeded crystallization of β-L-glutamic acid in a continuous oscillatory baffled crystallizer. Org Process Res Dev. 2015;19:1903–11.
Jiang M, Li Y-EED, Tung H-HH, Braatz RD. Effect of jet velocity on crystal size distribution from antisolvent and cooling crystallizations in a dual impinging jet mixer. Chem Eng Process Process Intensif Elsevier BV. 2015;97:242–7.
Alvarez AJ, Myerson AS. Continuous plug flow crystallization of pharmaceutical compounds. Cryst Growth Des. 2010;10:2219–28.
Hohmann L, Greinert T, Mierka O, Turek S, Schembecker G, Bayraktar E, et al. Analysis of crystal size dispersion effects in a continuous coiled tubular crystallizer: experiments and modeling. Cryst Growth Des. 2018;18:1459–73.
Eder RJP, Radl S, Schmitt E, Innerhofer S, Maier M, Gruber-Woelfler H, et al. Continuously seeded, continuously operated tubular crystallizer for the production of active pharmaceutical ingredients. Cryst Growth Des. 2010;10:2247–57.
Wiedmeyer V, Anker F, Bartsch C, Voigt A, John V, Sundmacher K. Continuous crystallization in a helically coiled flow tube: analysis of flow field, residence time behavior, and crystal growth. Ind Eng Chem Res. 2017;56:3699–712.
Han B, Ezeanowi NC, Koiranen TO, Häkkinen AT, Louhi-Kultanen M. Insights into design criteria for a continuous, sonicated modular tubular cooling crystallizer. Cryst Growth Des. 2018;18:7286–95.
Mou M, Li H, Yang B-S, Jiang M. Continuous generation of millimeter-sized glycine crystals in non-seeded millifluidic slug flow. Crystals. 2019;9:412.
Robertson K, Flandrin P-B, Klapwijk AR, Wilson CC. Design and evaluation of a mesoscale segmented flow reactor (KRAIC). Cryst Growth Des. 2016;16:4759–64.
Jiang M, Papageorgiou CD, Waetzig J, Hardy A, Langston M, Braatz RD. Indirect ultrasonication in continuous slug-flow crystallization. Cryst Growth Des. 2015;15:2486–92.
Jiang M, Zhu Z, Jimenez E, Papageorgiou CD, Waetzig J, Hardy A, et al. Continuous-flow tubular crystallization in slugs spontaneously induced by hydrodynamics. Cryst Growth Des. 2014;14:851–60.
Besenhard MO, Hohl R, Hodzic A, Eder RJP, Khinast JG. Modeling a seeded continuous crystallizer for the production of active pharmaceutical ingredients. Cryst Res Technol. 2014;49:92–108.
Rasche ML, Jiang M, Braatz RD. Mathematical modeling and optimal design of multi-stage slug-flow crystallization. Comput Chem Eng. 2016;95:240–8.
Besenhard MO, Neugebauer P, Scheibelhofer O, Khinast JG. Crystal engineering in continuous plug-flow crystallizers. Cryst Growth Des. 2017;17:6432–44.
Su M, Gao Y. Air-liquid segmented continuous crystallization process optimization of the flow field, growth rate, and size distribution of crystals. Ind Eng Chem Res. 2018;57:3781–91.
Rabesiaka M, Sghaier M, Fraisse B, Porte C, Havet JL, Dichi E. Preparation of glycine polymorphs crystallized in water and physicochemical characterizations. J Cryst Growth [Internet]. Elsevier; 2010;312:1860–1865. Available from: https://doi.org/10.1016/j.jcrysgro.2010.03.011
Hamilton BD, Hillmyer MA, Ward MD. Glycine polymorphism in nanoscale crystallization chambers. Cryst Growth Des. 2008;8:3368–75.
Bonnin-Paris J, Stéphane B, Jean-Louis H, Fauduet H. Determination of the metastable zone width of Glycine aqueous solutions for batch crystallizations. Chem Eng Commun. 2011;198:1004–17.
Moscosa-Santillán M, Bals O, Fauduet H, Porte C, Delacroix A. Study of batch crystallization and determination of an alternative temperature-time profile by on-line turbidity analysis-application to glycine crystallization. Chem Eng Sci. 2000;55:3759–70.
Little LJ, Sear RP, Keddie JL. Does the γ polymorph of glycine nucleate faster? A quantitative study of nucleation from aqueous solution. Cryst Growth Des. 2015;15:5345–54.
Dandekar P, Kuvadia ZB, Doherty MF. Engineering crystal morphology. Annu Rev Mater Res. 2013;43:359–86.
Renuka Devi K, Gnanakamatchi V, Srinivasan K. Attainment of unstable β nucleation of glycine through novel swift cooling crystallization process. J Cryst Growth [Internet]. 2014;400:34–42. Elsevier; Available from:. https://doi.org/10.1016/j.jcrysgro.2014.04.029.
He G, Bhamidi V, Wilson SR, Tan RBH, Kenis PJA, Zukoski CF. Direct growth of γ-glycine from neutral aqueous solutions by slow, evaporation-driven crystallization. Cryst Growth Des. 2006;6:1746–9.
Srinivasan K. Crystal growth of α and γ glycine polymorphs and their polymorphic phase transformations. J Cryst Growth. 2008;311:156–62.
Bhat MN, Dharmaprakash SM. Effect of solvents on the growth morphology and physical characteristics of nonlinear optical γ-glycine crystals. J Cryst Growth. 2002;242:245–52.
Neugebauer P, Cardona J, Besenhard MO, Peter A, Gruber-Woelfler H, Tachtatzis C, et al. Crystal shape modification via cycles of growth and dissolution in a tubular crystallizer. Cryst Growth Des. 2018;18:4403–15.
Kudo S, Takiyama H. Production of fine organic crystalline particles by using milli segmented flow crystallizer. J Chem Eng Jpn. 2012;45:305–9.
Perlovich GL, Hansen LK, Bauer-Brandl A. The polymorphism of glycine: thermochemical and structural aspects. J Therm Anal Calorim. 2001;66:699–715.
Netzel J, Hofmann A, Van Smaalen S. Accurate charge density of α-glycine by the maximum entropy method. CrystEngComm. 2008;10:335–43.
Langan P, Mason SA, Myles D, Schoenborn BP. Structural characterization of crystals of α-glycine during anomalous electrical behaviour. Acta Crystallogr Sect B Struct Sci International Union of Crystallography. 2002;58:728–33.
Barrett P, Smith B, Worlitschek J, Bracken V, O’Sullivan B, O’Grady D. A review of the use of process analytical technology for the understanding and optimization of production batch crystallization processes. Org Process Res Dev. 2005;9:348–55.
Chen J, Sarma B, Evans JMBB, Myerson AS. Pharmaceutical crystallization. Cryst Growth Des American Chemical Society. 2011;11:887–95.
Jiang Q, Shtukenberg AG, Ward MD, Hu C. Non-topotactic phase transformations in single crystals of β-glycine. Cryst Growth Des. 2015;15:2568–73.
Daniel Scott C, Labes R, Depardieu M, Battilocchio C, Davidson MG, Ley SV, et al. Integrated plug flow synthesis and crystallisation of pyrazinamide. React Chem Eng. 2018;3:631–4.
Majumder A, Nagy ZK. Fines removal in a continuous plug flow crystallizer by optimal spatial temperature profiles with controlled dissolution. AICHE J. 2013;59:4582–94.
Giulietti M, Seckler MM, Derenzo S, Ré MI, Cekinski E. Industrial crystallization and precipitation from solutions: state of the technique. Brazilian J Chem Eng SCIELO. 2001;18:423–40.
Vesga MJ, McKechnie D, Mulheran PA, Johnston K, Sefcik J. Conundrum of γ glycine nucleation revisited: to stir or not to stir? CrystEngComm Royal Society of Chemistry. 2019;21:2234–43.
Anbu Chudar Azhagan S, Kathiravan VS, Sathiya Priya N. Crystallization, habit modification and control of nucleation of glycine polymorphs from aqueous solutions doped with magnesium sulfate impurity. Mater Sci Pol. 2018;36:483–93.
Di Profio G, Tucci S, Curcio E, Drioli E. Selective glycine polymorph crystallization by using microporous membranes. Cryst Growth Des. 2007;7:526–30.
Virginia Commonwealth University is acknowledged for the financial support.
Conflict of Interest
The authors declare that they have no conflict of interest.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic Supplementary Material
About this article
Cite this article
Mou, M., Jiang, M. Fast Continuous Non-Seeded Cooling Crystallization of Glycine in Slug Flow: Pure α-Form Crystals with Narrow Size Distribution. J Pharm Innov 15, 281–294 (2020). https://doi.org/10.1007/s12247-020-09438-0
- Continuous crystallization
- Cooling nucleation
- Slug flow