A new conformational polymorph of N-acetyl-l-cysteine. The role of S–H⋯O and C–H⋯O interactions

Abstract

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 P2₁2₁2₁ 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⋯OC–CH₃ hydrogen bonds, except that the COOH group is rotated by 180° in form II to make an auxiliary C–H⋯O interaction with the methyl group in a R²₂(8) ring motif. The known form I contains weak S–H⋯OC–OH and N–H⋯S hydrogen bonds whereas the new form II has only N–H⋯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 ¹³C 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.