Polymorphic Control and Scale-Up Strategy for Antisolvent Crystallization Using Direct Nucleation Control

Iben Ostergaard, Botond Szilagyi, Heidi Lopez De Diego, Haiyan Qu*, Zoltan K. Nagy

*Corresponding author for this work

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In this work, a scale-up strategy based on the principles of direct design and quality-by-control (QbC) was applied and investigated using direct nucleation control (DNC). Process analytical technologies (PATs) were implemented for process monitoring and control. Antisolvent crystallization of indomethacin (IMC) was performed in a ternary solvent and antisolvent system. Mixture of acetone-methanol (66.5-33.5 wt %) was used as solvent and water as antisolvent since the mixed solvent system provides increased process yield and facilitates the suppression of the undesired acetone solvate. The effect of different process parameters, such as seed load, seed size, and initial concentration was investigated on process time, solid form and particle size distribution (PSD). The simplified solvent and antisolvent addition profiles obtained from the DNC were implemented directly in open-loop control to investigate reproducibility of the designed process. The open-loop operation was successfully scaled up by 1 order of magnitude, obtaining crystalline products with similar properties (solid form and PSD) as in the small-scale experiments. The results provide a proof-of-concept showing how the direct design approach can be applied in the rapid development of a robust crystallization process and efficient scale-up to yield the desired solid form with desired particulate properties (unimodal PSD and no agglomeration).

Original languageEnglish
JournalCrystal Growth & Design
Issue number4
Pages (from-to)2683-2697
Publication statusPublished - 1. Apr 2020


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