title: 35Cl dynamic nuclear polarization solid-state NMR of active pharmaceutical ingredients.
abstract: In this work, we show how to obtain efficient dynamic nuclear polarization (DNP) enhanced35Cl solid-state NMR (SSNMR) spectra at 9.4 T and demonstrate how they can be used to characterize the molecular-level structure of hydrochloride salts of active pharmaceutical ingredients (APIs) in both bulk and low wt% API dosage forms.35Cl SSNMR central-transition powder patterns of chloride ions are typically tens to hundreds of kHz in breadth, and most cannot be excited uniformly with high-power rectangular pulses or acquired under conditions of magic-angle spinning (MAS). Herein, we demonstrate the combination of DNP and1H-35Cl broadband adiabatic inversion cross polarization (BRAIN-CP) experiments for the acquisition of high quality wideline spectra of APIs under static sample conditions, and obtain signals up to 50 times greater than in spectra acquired without the use of DNP at 100 K. We report a new protocol, called spinning-on spinning-off (SOSO) acquisition, where MAS is applied during part of the polarization delay to increase the DNP enhancements and then the MAS rotation is stopped so that a wideline35Cl NMR powder pattern free from the effects of spinning sidebands can be acquired under static conditions. This method provides an additional two-fold signal enhancement compared to DNP-enhanced SSNMR spectra acquired under purely static conditions. DNP-enhanced35Cl experiments are used to characterize APIs in bulk and dosage forms with Cl contents as low as 0.45 wt%. These results are compared to DNP-enhanced1H-13C CP/MAS spectra of APIs in dosage forms, which are often hindered by interfering signals arising from the binders, fillers and other excipient materials.
authors.affiliation: Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON N9B 3P4, Canada. rschurko@uwindsor.ca.
authors.forename: David A
authors.initials: DA
authors.lastname: Hirsh
authors.affiliation: Department of Chemistry, Iowa State University, Ames, IA 50011, USA. arossini@iastate.edu and US DOE Ames Laboratory, Ames, Iowa 50011, USA.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Rossini
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, CH-1015, Switzerland.
authors.forename: Lyndon
authors.initials: L
authors.lastname: Emsley
authors.affiliation: Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON N9B 3P4, Canada. rschurko@uwindsor.ca.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Schurko
mesh_terms: D000551:Ambroxol / Q000737:chemistry; D017332:Cetirizine / Q000737:chemistry; D002713:Chlorine / Q000737:chemistry; D004155:Diphenhydramine / Q000737:chemistry; D006639:Histidine / Q000737:chemistry; D007556:Isoxsuprine / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D004364:Pharmaceutical Preparations / Q000737:chemistry; D012492:Salts / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D004364:Pharmaceutical Preparations; D012492:Salts; D000551:Ambroxol; D006639:Histidine; D002713:Chlorine; D004155:Diphenhydramine; D007556:Isoxsuprine; D017332:Cetirizine