(125d) Comparison of Isolation-Free Continuous Crystallization Operations: Falling Film Solution Layer Crystallization and Confined Suspension Crystallization

Continuous Manufacturing and Flow Synthesis have seen significant interest and uptake within the pharmaceutical industry. This has been driven by a number of distinct advantages over traditional batch chemistry and manufacturing approaches. Compared to batch processing continuous flow provides improved heat and mass transfer, selectivity and process intensity that enables improved safety, capital costs, and accessibility to a significantly wider range of process scale chemistries. In-spite of these advantages continuous synthesis and particularly multiple step integrated flow syntheses, that characterize the relatively complex continuous synthetic active pharmaceutical ingredient (API) routes have limitations in comparison to batch manufacturing of clinical and commercial supplies, requiring significant telescoping, which constrains the ability to provide intermediate purification, relies heavily on liquid extraction and increases complexity in process development. Batch synthetic routes are characterized by steps which typically are demarked by an intermediate crystallization, these steps enable subsequent steps to begin with unconstrained solvent choice, optimal concentration and purified intermediate feeds. This aligns well with the almost unique combination of purity, regulatory requirements, constrained development timescales, uncertainty of product commercialization and need for flexibility that characterize pharmaceutical development.

This study aims to build upon the previous demonstration of isolation free crystallization^1,2via falling film solution layer crystallization to provide the ability to conduct significant intermediate purification and solvent swapping via crystallization without the need for isolation, thus allowing many of the flexibilities and advantages of batch manufacturing to be retained in fully telescoped multi-step continuous synthesis. Falling film solution layer crystallization ^1,2is conducted in a novel low-cost modular 3D printed configuration in this study. Its performance is compared to confined suspension crystallization an approach outlined here where suspended solids are retained within a crystallization volume rather than confined to a layer. Both operations negate the need to conduct standard continuous crystallisations with isolation and redissolution for intermediate purification in telescoped flow synthesis.

References

1. N Yazdanpanah, ST Ferguson, AS Myerson, BL Trout. Crystal Growth & Design 16 (1), 285-296
2. N Yazdanpanah, AS Myerson, BL Trout. Ind. Eng. Chem. Res., 2016, 55 (17), pp 5019 –5029