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

Abstract

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.

Abstract

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.