In this study, we have measured 35Cl/ 1H correlations in hydrochloride salts of active pharmaceutical ingredients (HCl APIs) using the D-HMQC pulse sequence at fast MAS.
The determination of structure of hydrochloride salts of active pharmaceutical ingredients (HCl APIs) utilizing 35Cl solid-state NMR studies has been of considerable interest in the recent past. Until now these studies relied on the 35Cl 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 35Cl. In this contribution we demonstrate the two-dimensional (2D) 35Cl/ 1H correlation measurement by using the proton detection-based (indirect observation of 35Cl via 1H) 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 35Cl– 1H heteronuclear dipolar interactions. The applicability of 35Cl indirect detection method is first demonstrated on hydrochloride salts of amino acids, l-tyrosine·HCl and l-histidine·HCl·H 2O following which the 2D 35Cl/ 1H correlations are obtained for HCl APIs, procainamide HCl (Proc) 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 35Cl/ 1H correlations provide the precise determination of 1H chemical shifts of nearby 35Cl nuclei.