Antisolvent Crystallization of Indomethacin from a Ternary Solvent System with High Productivity, Better Polymorphism, and Particle Size Control

Chandrakant Ramkrishna Malwade*, Haiyan Qu

*Corresponding author for this work

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Abstract

Antisolvent crystallization of indomethacin (IMC), a nonsteroidal anti-inflammatory drug, from a ternary solvent system (acetone–methanol–water) has been investigated in this work. The acetone–methanol (66.5–33.5 wt %) binary mixture was selected as a solvent on the basis of the solubility of IMC reported earlier. Water was selected as an antisolvent on the basis of the solubility of IMC measured in acetone–methanol–water mixtures at 25 °C. Unseeded and seeded antisolvent crystallization was carried out for two initial concentrations of IMC (C0,1 and C0,2) with the stepwise addition of antisolvent. The acetone solvate of IMC was crystallized during the unseeded experiments, while the desired γ-IMC was obtained with a bimodal particle size distribution (PSD) during the experiments seeded with γ-IMC. A significant increase in the productivity was observed because of increased crystal yield and faster crystallization kinetics as compared to those of the crystallization processes reported earlier for the production of γ-IMC. Finally, the feasibility of IMC particle size tuning through the solvent–antisolvent (dissolution–growth) addition cycles was demonstrated successfully.
Original languageEnglish
JournalOrganic Process Research & Development
Volume23
Issue number5
Pages (from-to)968-976
ISSN1083-6160
DOIs
Publication statusPublished - 17. May 2019

Keywords

  • antisolvent crystallization
  • indomethacin
  • particle size distribution
  • polymorphism
  • solubility

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