Structural study of salt forms of amides; paracetamol, benzamide and piperine

Single crystal x-ray diffraction has been used to investigate the structures of six complexes containing O-atom protonated cations derived from the pharmaceutically relevant amides benzamide (BEN), paracetamol (PAR) and piperine (PIP). The structures of the salt forms [PAR(H)][SO₃C₆H₄Cl], [BEN(H)][O₃SC₆H₄Cl] and [BEN(H)][Br].H₂O are reported along with those of the hemi-halide salt forms [PAR(H)][I₃].PAR , [PIP(H)][I₃].PIP and [PIP(H)][I₃]_0.5[I]_0.5.PIP. The structure of the cocrystal BEN.HOOCCH₂Cl is also presented for comparison. The geometry of the amide group is found to systematically change upon protonation, with the C=O distance increasing and the C-N distance decreasing. The hemi-halide species all feature strongly hydrogen bonded amide(H)/amide pairs. The amide group C=O and C-N distances for both elements of each such pair are intermediate between those found for simple neutral amide and protonated amide forms. It was found that crystallising paracetamol from aqueous solutions containing Ba²⁺ ions gave orthorhombic paracetamol.