A new conformational polymorph of N-acetyl-L-cysteine. The role of S-H•••O and C-H•••O interactions

A novel polymorph of N-acetyl-L-cysteine (NAC) is discovered three decades after the first report on the X-ray crystal structure of this bioactive compound. The crystal structure of the new orthorhombic polymorph (form II in the P2(1)2(1)2(1) space group) is characterized by X-ray diffraction and compared to the triclinic structure of form I (NALCYS02 and NALCYS10 in the P1 space group). Both polymorphs contain a C(7) chain of COOH center dot center dot center dot O=C-CH3 hydrogen bonds, except that the COOH group is rotated by 180 degrees in form II to make an auxiliary C-H center dot center dot center dot O interaction with the methyl group in a R-2(2)(8) ring motif. The known form I contains weak S-H center dot center dot center dot O=C-OH and N-H center dot center dot center dot S hydrogen bonds whereas the new form II has only N-H center dot center dot center dot S interactions. The conformational polymorphs of NAC were compared by Hirshfeld surface analysis (d(norm)) and XPac methods, and were spectroscopically characterized by FT-IR and Raman spectroscopy. The bulk phases were distinguished by their C-13 ss-NMR and powder X-ray diffraction line patterns. The two polymorphs are enantiotropically related (form I has a higher melting temperature and lower enthalpy of fusion). However, no phase transition was observed in the DSC analysis. The metastable form II converted to stable form I in solid-state grinding, a slurry medium and storage in ambient conditions for 3 months.