(189f) Continuous Pharmaceutical Manufacturing of Uniform Crystals in Slug Flow

In the pharmaceutical and chemical industries, the continuous generation of crystals of target size distribution has the potential to improve efficiency for post-crystallization operations^1–7. The control of crystallization processes can be challenging when undesirable phenomena such as particle attrition and breakage occur. Segmented/slug flow crystallization is one of the effective continuous processes demonstrated to allow enhanced control of organic crystal properties such as size and shape^2–7. 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.

This presentation will elaborate: (1) the process design and strategies for continuous slug-flow crystallization that controls the crystallization phenomena; (2) the tuning of crystal properties without changing the equipment set-up⁴. Process intensification strategy is also discussed which makes the whole process more robust. Experimental validation confirms that the proposed crystallizer designs reduce production time and equipment cost evidently while suppressing secondary nucleation, attrition, and aggregation—dominant but undesired phenomena that worsen the ability to control the crystal properties.

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.