(504d) Controlled Nucleation Via Continuous Mode of Processing for Robust API Crystallization

Controlled crystallization of active pharmaceutical ingredient (API) from solution is an economical way of producing API with desired physical-chemical properties (or critical quality attributes, CQAs). The common CQAs range from purity, polymorph, residual solvent content to particle size distribution, morphology, density, flow property, etc.. Some common challenges in developing robust API crystallization processes for production, meeting product CQAs, include a) achieving consistent seeding control, b) prevention of uncontrolled nucleation, and c) addressing variation during batch scale-up. It is inherently challenging to scale up crystallization processes involving nucleation in batch reactors due to complex fluid dynamic variations at different scales and configurations. This talk will share methodologies based on nucleation dynamics for the design and control of scalable API crystallization processes. Case studies applying process intensification in continuous mode of operation will be presented, with the goal to enable reproducible self-seeding and subsequent crystal growth, therefore achieving robust PSD and polymorph controls. PAT tools are used in the process development to monitor and assess the crystallization dynamics and enable efficient process optimization.