Two-dimensional proton-detected 35Cl/1H correlation solid-state NMR experiment under fast magic angle sample spinning: application to pharmaceutical compounds

The determination of structure of hydrochloride salts of active pharmaceutical ingredients (HCl APls) utilizing Cl-35 solid-state NMR studies has been of considerable interest in the recent past. Until now these studies relied on the Cl-35 direct observation method which has its own limitations in terms of the sensitivity and resolution due to the quadrupolar nature and the low gyromagnetic ratio of Cl-35 . In this contribution we demonstrate the two-dimensional (2D) Cl-35/H-1 correlation measurement by using the proton detection-based (indirect observation of Cl-35 via H-1) approach under fast magic angle sample spinning (MAS: 70 kHz). The main advantages of this approach over the direct observation method are highlighted in the present study. We have employed heteronuclear magnetization transfer through the recoupling of Cl-35-H-1 heteronuclear dipolar interactions. The applicability of Cl-35 indirect detection method is first demonstrated on hydrochloride salts of amino acids, L-tyrosine.HCl and L-histidine.HCl.H2O following which the 2D Cl-35/H-1 correlations are obtained for HCl APls, procainamide HCl (Prot) and aminoguanidine HCl (Amin). On the basis of separation between the central transition (CT) and satellite transition (ST) peaks, and the shape/width of CT powder patterns, it is also shown that the quadrupolar parameters which are useful for the elucidation of the molecular structure can be determined. Moreover, the Cl-35/H-1 correlations provide the precise determination of H-1 chemical shifts of nearby Cl-35 nuclei.