Recent Progress in Continuous Crystallization

Dear Colleagues,

The recent SARS-CoV-2 pandemic underlines the need for rapid, scalable, and robust operation of pharmaceutical manufacturing systems that permits flexible production of lifesaving drugs quickly and safely when needed. Continuous pharmaceutical manufacturing is encouraged by the world-leading regulatory agencies due to several advantages over batch manufacturing. Potential advantages include a more consistent product quality, improved safety, easier scalability and the resilience of a fully automated end-to-end production system. In contrast, batch-wise production is characterized by intermittent operation and often intercontinental shipping of intermediates. Crystallization not only separates and purifies the intermediates/final drug substance in each synthesis step, but also constitutes the bridge between the synthesis of the drug substance and the final product formulation in terms of polymorphs, particle size distribution, shape, and so on. Therefore, it has an indispensable role in a fully continuous, integrated pharmaceutical manufacturing system. The increasing number of industrial applications and journal publications underlines the high attention on this topic, which motivates the current Special Issue.

The aim of this Special Issue is to capture the most recent advances and innovations in the area of continuous pharmaceutical crystallization. Industrial applications involving process development for real APIs at any scale is the main focus. Furthermore, work on fundamental advancements is also warmly welcomed. Topics of interest include, but are not limited to:

• Fundamentals of crystallization kinetics and thermodynamics, impurity rejection, phase diagrams, and liquid–liquid phase separation;
• Development and application of process analytical technology (PAT) and innovative monitoring strategies;
• Multivariable data analysis and machine learning in complex monitoring systems;
• Advanced control methods;
• On-line fault diagnosis, troubleshooting and predictive maintenance with particular focus on fouling issues and antifouling strategies;
• Integration with upstream (e.g. reaction) and downstream (e.g. filtration and drying) processes;
• Application of quality by design (QbD) and quality by control (QbC) approaches for the design of innovative crystallization systems;
• Integration with particle size and shape manipulating steps, including ultrasound, wet-milling and spherical agglomeration;
• CFD simulations for process scale-up;
• High throughout crystallization screening, solvent selection, and design;
• Techno-economic optimizations, environmental impacts;
• Industrial case studies of integrated continuous pharmaceutical processes.

We are pleased to invite you to contribute to this Special Issue in form of a review paper or original research article.

Dr. Botond Szilágyi
Dr. Qinglin Su
Dr. Richard Lakerveld
Guest Editors

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