Nonclassical Crystallization and Core-Shell Structure Formation of Ibuprofen from Binary Solvent Solutions

Rajaboopathi Mani, Leena Peltonen, Clare J. Strachan, Maarit Karppinen, Marjatta Louhi-Kultanen

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Liquid-liquidphase separation (LLPS) or dense liquid intermediates during the crystallization of pharmaceutical molecules is common; however, their role in alternative nucleation mechanisms is less understood. Herein, we report the formation of a dense liquid intermediate followed by a core-shell structure of ibuprofen crystals via nonclassical crystallization. The Raman and SAXS results of the dense phase uncover the molecular structural ordering and its role in nucleation. In addition to the dimer formation of ibuprofen, which is commonly observed in the solution phase, methyl group vibrations in the Raman spectra show intermolecular interactions similar to those in the solid phase. The SAXS data validate the cluster size differences in the supersaturated solution and dense phase. The focused-ion beam cut image shows the attachment of nanoparticles, and we proposed a possible mechanism for the transformation from the dense phase into a core-shell structure. The unstable phase or polycrystalline core and its subsequent dissolution from inside to outside or recrystallization by reversed crystal growth produces the core-shell structure. The LLPS intermediate followed by the core-shell structure and its dissolution enhancement unfold a new perspective of ibuprofen crystallization.

Original languageEnglish
Pages (from-to)236-245
Number of pages10
JournalCrystal Growth and Design
Issue number1
Early online date21 Dec 2022
Publication statusPublished - 4 Jan 2023
MoE publication typeA1 Journal article-refereed


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