Automated direct nucleation control for in situ dynamic fines removal in batch cooling crystallization

Analysis of the crystallization process of a biopharmaceutical compound in the presence of impurities using process analytical technology (PAT) tools

“…Four cooling rates were used: –0.075, –0.1, –0.5 and –1°C min −1 (slower, slow, fast and faster cooling), both seeded and unseeded experiments were performed. The cooling rates were chosen based on experience with similar types of crystals, equipment and scale . The final temperature after cooling was 5–6°C.…”

Advanced control approaches for combined cooling/antisolvent crystallization in continuous mixed suspension mixed product removal cascade crystallizers

“…The applications of both approaches in batch crystallization have been studied in depth in literature. Model-free approaches, such as direct nucleation control (DNC) (Abu Bakar et al, 2009;Saleemi et al, 2012), or supersaturation control (SSC) (Gron et al, 2003;Nagy and Aamir, 2012) are methodologies that maintain the operating curve within the metastable zone to avoid or control nucleation or generate controlled dissolution. For model-based approaches, typically a population balance model (PBM) is used to describe the evolution of the CSD in the crystallization process and to obtain open-loop optimal temperature or/and antisolvent addition profiles that can produce desired CSD (Acevedo and Nagy, 2014;Rawlings et al, 1993;Xie et al., 2001;Zhang and Rohani, 2003).…”

Oscillatory Flow Reactors (OFRs) for Continuous Manufacturing and Crystallization

“…100 -500 µm), high quality crystals, which can be reproduced consistently, are typically desired for industrial crystallization processes. Several factors contribute to the final CSD including primary 27 and secondary 28 nucleation, growth, agglomeration, attrition and crystal breakage, encrustation, disturbances to the metastable zone width (MSZW, 26,27,29 see Figure 1) such as an impurity profile, polymorphism, agglomeration/aggregation, solvates and hydrates and seeding. Conventional approaches for obtaining crystals of a desired crystal form and size distribution have suffered from batch-to-batch variability, particularly at the manufacturing scale.…”