(268b) Scalable Modular Manufacturing of Amino Acid Crystals with Improved Uniformity

The pharmaceutical and chemical industry has increased demands for reproducible and efficient green manufacturing of crystalline products. For many key ingredients of these products (e.g., amino acids), uniformity and consistency in quality across different scales/stages is a must, and a huge challenge for existing batch processes.^1–8 This talk focuses on the slug-flow (or segmented flow) crystallizer design, which is one of the effective continuous processes demonstrated to allow enhanced control of organic crystal properties such as size and shape^2–8. The slurry flow is combined with an air flow and fed to a tube to induce a multiphase hydrodynamic instability that spontaneously generates well-mixed slugs where the crystals continue to grow. Experimental validation confirms that the proposed designs reduce development time by orders of magnitude while suppressing secondary nucleation, attrition, and clogging/fouling—dominant but undesired phenomena that worsen the ability to quality control.

References

(1) Sun, Z.; Ya, N.; Adams, R. C.; Fang, F. S. Particle Size Specifications for Solid Oral Dosage Forms: A Regulatory Perspective. Am. Pharm. Rev. 2010, 13 (4).

(2) Jiang, M.; Zhu, Z.; Jimenez, E.; Papageorgiou, C. D.; Waetzig, J.; Hardy, A.; Langston, M.; Braatz, R. D. Continuous-Flow Tubular Crystallization in Slugs Spontaneously Induced by Hydrodynamics. Cryst. Growth Des. 2014, 14 (2), 851–860.

(3) Eder, R. J. P.; Schrank, S.; Besenhard, M. O.; Roblegg, E.; Gruber-Woelfler, H.; Khinast, J. G. Continuous Sonocrystallization of Acetylsalicylic Acid (ASA): Control of Crystal Size. Cryst. Growth Des. 2012, 12 (10), 4733–4738.

(4) Jiang, M.; Papageorgiou, C. D.; Waetzig, J.; Hardy, A.; Langston, M.; Braatz, R. D. Indirect Ultrasonication in Continuous Slug-Flow Crystallization. Cryst. Growth Des. 2015, 15 (5), 2486–2492.

(5) 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 (10), 3781–3791.

(6) Daniel Scott, C.; Labes, R.; Depardieu, M.; Battilocchio, C.; Davidson, M. G.; Ley, S. V.; Wilson, C. C.; Robertson, K. Integrated Plug Flow Synthesis and Crystallisation of Pyrazinamide. React. Chem. Eng. 2018, 3 (5), 631–634.

(7) Lu, J.; Litster, J. D.; Nagy, Z. K. Nucleation Studies of Active Pharmaceutical Ingredients in an Air-Segmented Microfluidic Drop-Based Crystallizer. Cryst. Growth Des. 2015, 15 (8), 3645–3651.

(8) 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. 2020. https://doi.org/10.1007/s12247-020-09438-0.