The mixing criterion in crystallization by cooling

Toussaint, Aurore; Donders, A.J.M.

doi:10.1016/0009-2509(74)85049-9

Cited by 6 publications

(1 citation statement)

References 2 publications

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“…Accumulation of solids can result from adhesion of existing particles to internal surfaces of a crystallizer, or nucleation and growth on the surface. It has generally been known and accepted that higher supersaturation leads to higher fouling rates. − In the work by Steendam and ter Horst, modifying process conditions such as increasing τ reduced the fouling in the crystallization of pure enantiomer from a mixture . In other examples, minimizing supersaturation has been one of the most effective ways to minimize fouling rate and remain within the metastable zone width (MSZW) by keeping the system close to the equilibrium solubility. , Continuous seeding has proven to reduce fouling in tubular crystallizers by providing a large surface area for growth on particle surfaces, which consequently lowers supersaturation .…”

Section: Literature Reviewmentioning

confidence: 99%

API Continuous Cooling and Antisolvent Crystallization for Kinetic Impurity Rejection in cGMP Manufacturing

Johnson

Burcham

May

et al. 2021

Org. Process Res. Dev.

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Crystallization of 204 kg of final active pharmaceutical ingredient was accomplished continuously using a cascade of mixed suspension mixed product removal crystallizers in cGMP manufacturing. This article describes the journey taken to transform a set of technical to final batch crystallizations into a continuous, combined cooling and antisolvent crystallization using three stirred tank crystallizers in series. Conversion of the batch process to a continuous process was beneficial to kinetically purge a key impurity. The conversion also allowed for the direct integration of the crystallization process with upstream continuous chemistry sections. A robust control strategy was developed from early research scale all the way to cGMP manufacturing. The authors will share the tools, techniques, modeling, and equipment used and challenges overcome to ensure a safe and reliable manufacturing process. A new intermittent flow technique transferred hot solution from a continuous evaporator into the first crystallizer with no solids bearding at the end of the inlet tubing. The continuous distillation, crystallization, and slurry-off filters were a key part of a broader continuous process and new building that won an International Society for Pharmaceutical Engineering 2019 Facility of the Year Award for Innovation.

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