Investigation of wet milling and indirect ultrasound as means for controlling nucleation in the continuous crystallization of an active pharmaceutical ingredient

Yihui Yang, Bilal Ahmed, Christopher Mitchell, Justin L. Quon, Humera Siddique, Ian Houson, Alastair J. Florence, Charles D. Papageorgiou

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Abstract

This study compares the use of wet milling and indirect ultrasound for promoting nucleation and controlling the particle size during the continuous crystallization of a hard-to-nucleate active pharmaceutical ingredient (API). Both an immersion and an external wet mill installed on a recirculation loop were investigated. It was found that all methodologies significantly improved the nucleation kinetics, and the effects of key process parameters (e.g., mill speed, temperature, and ultrasound intensity) on particle size were experimentally investigated. A minimum d50 of 27 and 36.8 μm was achieved when using the wet mill and ultrasound, respectively. The effectiveness of wet milling was demonstrated in a three-stage mixed suspension mixed product removal continuous crystallization of the API that was operated continuously for 12 h (eight residence times), achieving a steady state with minimal fouling. Strategies for improving the overall robustness of the setup in routine manufacturing are discussed.
Original languageEnglish
Pages (from-to)2119-2132
Number of pages14
JournalOrganic Process Research and Development
Volume25
Issue number9
Early online date1 Sep 2021
DOIs
Publication statusPublished - 17 Sep 2021

Keywords

  • wet milling
  • ultrasound
  • continuous crystallization
  • fouling
  • mixed suspension
  • mixed product removal crystallizer
  • crystallization

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