Polymorphic Control and Scale-Up Strategy for Antisolvent Crystallization Using a Sequential Supersaturation and Direct Nucleation Control Approach

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

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

In this work, a rapid direct design approach for crystallization processes was implemented using the novel Quality-by-Control (QbC) framework by sequentially applying antisolvent-based super-saturation control (AS-SSC) and temperature driven direct nucleation control (T-DNC) strategies. This novel strategy was used to optimize and scale up the batch crystallization of indomethacin (IMC) from a ternary solvents/antisolvent system, which enables the production of the desired polymorphic γ form with significantly increased process yield. Sequentially applying the supersatu-ration control (SSC) and direct nucleation control (DNC) led to a combination of the advantages of the two feedback control strategies. SSC-based direct design and scale-up strategy showed high efficiency in providing high productivity (high process yield and shorter batch time), whereas DNC is advantageous in ensuring reproducible particle size distribution from processes at different scales. The combined AS-SSC and T-DNC strategy presented in this work showed a promising syn-ergy, which enabled a good balance between the high productivity of the crystallization process and reproducible crystal properties from the processes at different scales. The results provide a proof-of-concept showing that the proposed QbC approach based on the sequential SSC-DNC im-plementation can be applied for rapid and successful scale-up, leading to similar particulate prop-erties across scales.
Original languageEnglish
JournalCrystal Growth & Design
Volume20
Issue number8
Pages (from-to)5538-5550
ISSN1528-7483
DOIs
Publication statusPublished - 5. Aug 2020

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