Natural abundance N and N solid-state NMR of pharmaceuticals and their polymorphs

• Published in: Physical chemistry chemical physics : PCCP 2016-06, Vol.18 (26), p.17713-1773
• Main Authors: Veinberg, Stanislav L, Johnston, Karen E, Jaroszewicz, Michael J, Kispal, Brianna M, Mireault, Christopher R, Kobayashi, Takeshi, Pruski, Marek, Schurko, Robert W
• Format: Article
• Language: English
• ISSN: 1463-9076; 1463-9084
• DOI: 10.1039/c6cp02855a

14 N ultra-wideline (UW), 1 H{ 15 N} indirectly-detected HETCOR (idHETCOR) and 15 N dynamic nuclear polarization (DNP) solid-state NMR (SSNMR) experiments, in combination with plane-wave density functional theory (DFT) calculations of 14 N EFG tensors, were utilized to characterize a series of nitrogen-containing active pharmaceutical ingredients (APIs), including HCl salts of scopolamine, alprenolol, isoprenaline, acebutolol, dibucaine, nicardipine, and ranitidine. A case study applying these methods for the differentiation of polymorphs of bupivacaine HCl is also presented. All experiments were conducted upon samples with naturally-abundant nitrogen isotopes. For most of the APIs, it was possible to acquire frequency-stepped UW 14 N SSNMR spectra of stationary samples, which display powder patterns corresponding to pseudo-tetrahedral ( i.e. , RR′R′′NH + and RR′NH 2 + ) or other ( i.e. , RNH 2 and RNO 2 ) nitrogen environments. Directly-excited 14 N NMR spectra were acquired using the WURST-CPMG pulse sequence, which incorporates WURST (wideband, uniform rate, and smooth truncation) pulses and a CPMG (Carr-Purcell Meiboom-Gill) refocusing protocol. In certain cases, spectra were acquired using 1 H → 14 N broadband cross-polarization, via the BRAIN-CP (broadband adiabatic inversion - cross polarization) pulse sequence. These spectra provide 14 N electric field gradient (EFG) tensor parameters and orientations that are particularly sensitive to variations in local structure and intermolecular hydrogen-bonding interactions. The 1 H{ 15 N} idHETCOR spectra, acquired under conditions of fast magic-angle spinning (MAS), used CP transfers to provide 1 H- 15 N chemical shift correlations for all nitrogen environments, except for two sites in acebutolol and nicardipine. One of these two sites (RR′NH 2 + in acebutolol) was successfully detected using the DNP-enhanced 15 N{ 1 H} CP/MAS measurement, and one (RNO 2 in nicardipine) remained elusive due to the absence of nearby protons. This exploratory study suggests that this combination of techniques has great potential for the characterization of solid APIs and numerous other organic, biological, and inorganic systems. 14 N and 15 N solid-state NMR at natural abundance are used in tandem for the investigation of pharmaceuticals and their polymorphs.