Anti-Solvent Crystallization

Dear Colleagues,

Anti-solvent crystallization is employed extensively in pharmaceutical and fine chemical industries for separation and purification purposes. It involves the mixing of two liquids, which adds to the complex interactions between thermodynamics and kinetics of crystallization. It is well known that the instantaneous local supersaturation at feeding points can reach an extremely high level if the solubility of solute changes fast with solvent composition. On the one hand, high supersaturation can cause deleterious effects on crystal products, i.e., generation of undesired solid forms, inadequate rejection of impurities, etc. On the other hand, it can be leveraged on to generate small particles with narrow size distribution that can be directly used in formulations without further size reduction.

Much work has been done in an effort to understand the mixing process and its effects on crystallization. Apart from experimental work, process modelling has been used to quantify the temporal and spatial influence of supersaturation on nucleation and growth. Microfluidic devices have been attempted to have more precise control over these temporal and spatial effects. With these progresses, the following topics are of industrial interest:

1. Trouble shooting of anti-solvent crystallization. Various quality issues may arise during anti-solvent crystallization, e.g., oiling out, appearance of undesired solid forms, unacceptable solvent residual or crystal habit, failure to pass clarity test or dissolution test, etc. It is rare that the results in a case study are directly applicable to other cases. However, the analysis and rationale in a case study can go a long way.
2. Solvent effects on crystallization. The choice of solvents/anti-solvents seems to be the most important decision in anti-solvent crystallization development. The mechanism of solvent effects is yet to be understood to speed up solvent screening.
3. Seeding has proved effective in mitigation of oiling out, polymorph and size control. However, arbitrary elements still exist in seeding protocol determination. Industrial experiences and understanding with seed preparation, assessment of seed qality and seed application will help with rational design of seeding protocols.
4. It has been demonstrated that aditives can effectively modify crystal habit, mitigate agglomeration and affect the generation of polymorphs. Notwithstanding, the addition of exogenous additives to crystallizers of pharmaceuticals is a regulatory concern. Discussions on the uses of additives in industrial context and exchange of views are warmly welcome.
5. Size reduction by anti-solvent crystallization. Micron-sized particles, usually prepared by milling, are needed for various delivery vehicles, including injectable suspension, inhaling powders, gel, etc. Anti-solvent crystallization is a promising alternaitve to milling. However, measures must be taken to address pratical problems in anti-solvent crystallization such as agglomeration during drying, Ostwald ripening, solvent residual, etc. Sharing of effective measures are especially encouraged.
6. Continuous anti-solvent crystallization. Crystallization step is a discontinuous point in continuous prcoessing of pharmaceuticals. Currently, continuous crystallization is afflicted by a few issues, such as blockage of piping, lower yield than batch crystallization, accumulation of impurities, etc. More work needs to be done to tackle these problems.

The list is not exhaustive. Any case studies or reviews on anti-solvent crystallization with practical values will be considered.

Prof. Dr. Reginald Beng Hee Tan
Dr. Zaiqun Yu
Guest Editors

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