Polymorphic Control and Scale-up Strategy for Crystallization from a Ternary Antisolvent System by Supersaturation Control

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

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

8 Downloads (Pure)

Abstract

Antisolvent crystallization of indomethacin (IMC) was investigated in this work by using an acetone-methanol (66.5-33.5 wt %) mixture as solvent and water as antisolvent. Selecting the binary mixture as the solvent led to an increased yield of the batch process, as the solubility of IMC is higher in the mixed solvents. Adding methanol to the solvent system mitigated the nucleation of the acetone solvate, which is dominating in the acetone-water system. Process analytical technologies were implemented to ensure that the desired polymorph was present throughout the process. Supersaturation control (SSC) was applied as a closed-loop feedback control strategy, to achieve a rapid direct design of the crystallization process using the principles of quality by control. The antisolvent flow-rate profiles, obtained by the SSC, were implemented in open loop and used for scaling up the process by 1 order of magnitude. The results show how feedback control of crystallization from a ternary solvent mixture increases productivity and simultaneously ensures suppression of nucleation to obtain the desired particle size distribution and polymorph. The direct design approach can be applied in the design and development of crystallization processes to yield the chosen solid phase of IMC when scaling from small to large scale.

Original languageEnglish
JournalCrystal Growth & Design
Volume20
Issue number2
Pages (from-to)1337-1346
ISSN1528-7483
DOIs
Publication statusPublished - 5. Feb 2020

Fingerprint Dive into the research topics of 'Polymorphic Control and Scale-up Strategy for Crystallization from a Ternary Antisolvent System by Supersaturation Control'. Together they form a unique fingerprint.

Cite this