p-Toluidinium nitrate

Abstract

The aim of the study of optical resolution processes is to achieve a more efficient and less time consuming way of enantiomer separation. Supercritical fluid extraction as an alternative green technology for optical isomer separation was applied for the resolution of ibuprofen. Ibuprofen is widely used as non-steroidal anti-inflammatory drug. The resolution of ibuprofen (1) with the mixture of (+)-(R)-phenylethylamine (2) and benzylamine (3) was compared to the results obtained without the achiral additive [1]. Single crystal X-ray studies were performed on the salts of (+)-(R)-phenylethylamine crystallized with (-)-(R)-ibuprofen (4) and (+)-(S)-ibuprofen (5) as well as on the co-crystal resulted from the crystallisation of the racemic ibuprofen with the achiral benzylamine (6) in order to study the influence of the structurally similar achiral additive. (+)-(R)-phenylethylamine crystallises with (-)-(R)ibuprofen and (+)-(S)-ibuprofen, respectively with 1:1 stoichiometry. Unexpectedly, the crystal of the benzylamineibuprofen salt contains an additional neutral ibuprofen molecule thus having 1:2 stoichiometry obtaining both from solution crystallisation and by mass balance calculation of the supercritical fluid CO 2 extraction. The lack of the methyl moiety in the benzylamine in structure (6) compared to the (+)-(R)-phenylethylamine molecule in structures (4) and (5) results a sterically favourable closer packing, higher crystal density. There is enough space in crystal (6) close to the ladder like hydrogen bond column to bond a neutral ibuprofen molecule as end group in the low acidity medium.