Two-dimensional proton-detected (35)Cl/(1)H correlation solid-state NMR experiment under fast magic angle sample...

Area of Science:

• Solid-state Nuclear Magnetic Resonance (NMR) Spectroscopy
• Pharmaceutical Analysis
• Materials Science

Background:

• Determining the structure of hydrochloride salts of active pharmaceutical ingredients (HCl APIs) is crucial for drug development.
• Traditional (35)Cl solid-state NMR methods face challenges in sensitivity and resolution due to the quadrupolar nature and low gyromagnetic ratio of (35)Cl.
• Existing techniques limit detailed structural elucidation of HCl APIs.

Purpose of the Study:

• To demonstrate a novel two-dimensional (2D) (35)Cl/(1)H correlation measurement using proton detection (indirect observation of (35)Cl via (1)H).
• To highlight the advantages of this indirect detection method over direct (35)Cl observation for HCl API structural analysis.
• To showcase the utility of this technique for determining molecular structures and (1)H chemical shifts.

Main Methods:

• Employed fast magic angle sample spinning (MAS) at 70 kHz.
• Utilized heteronuclear magnetization transfer via recoupling of (35)Cl-(1)H heteronuclear dipolar interactions.
• Applied the method to hydrochloride salts of amino acids (l-tyrosine·HCl, l-histidine·HCl·H2O) and HCl APIs (procainamide HCl, aminoguanidine HCl).

Main Results:

• Successfully obtained 2D (35)Cl/(1)H correlation spectra for various HCl salts.
• Demonstrated improved sensitivity and resolution compared to direct (35)Cl observation.
• Showed that quadrupolar parameters and (1)H chemical shifts near (35)Cl nuclei can be precisely determined.

Conclusions:

• The (35)Cl indirect detection method offers significant advantages for the structural determination of HCl APIs.
• This technique enables more accurate analysis of molecular structures by providing detailed quadrupolar and chemical shift information.
• The 2D (35)Cl/(1)H correlation NMR is a powerful tool for pharmaceutical solid-state characterization.