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Title: 35Cl dynamic nuclear polarization solid-state NMR of active pharmaceutical ingredients

Abstract

In this paper, we show how to obtain efficient dynamic nuclear polarization (DNP) enhanced 35Cl 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 and 1H– 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 wideline 35Cl 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 tomore » DNP-enhanced SSNMR spectra acquired under purely static conditions. DNP-enhanced 35Cl 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-enhanced 1H– 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.« less

Authors:
 [1];  [2];  [3];  [1]
  1. Univ. of Windsor, Windsor, ON (Canada)
  2. Iowa State Univ., Ames, IA (United States); Ames Lab., Ames, IA (United States)
  3. Ecole Polytechnique Federale Lausanne (Switzlerland)
Publication Date:
Research Org.:
Ames Laboratory (AMES), Ames, IA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1335033
Report Number(s):
IS-J-9134
Journal ID: ISSN 1463-9076; PPCPFQ
Grant/Contract Number:
AC02-07CH11358
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Physical Chemistry Chemical Physics. PCCP (Print)
Additional Journal Information:
Journal Name: Physical Chemistry Chemical Physics. PCCP (Print); Journal Volume: 18; Journal Issue: 37; Journal ID: ISSN 1463-9076
Publisher:
Royal Society of Chemistry
Country of Publication:
United States
Language:
English
Subject:
38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEAR CHEMISTRY

Citation Formats

Hirsh, David A., Rossini, Aaron J., Emsley, Lyndon, and Schurko, Robert W.. 35Cl dynamic nuclear polarization solid-state NMR of active pharmaceutical ingredients. United States: N. p., 2016. Web. doi:10.1039/c6cp04353d.
Hirsh, David A., Rossini, Aaron J., Emsley, Lyndon, & Schurko, Robert W.. 35Cl dynamic nuclear polarization solid-state NMR of active pharmaceutical ingredients. United States. doi:10.1039/c6cp04353d.
Hirsh, David A., Rossini, Aaron J., Emsley, Lyndon, and Schurko, Robert W.. 2016. "35Cl dynamic nuclear polarization solid-state NMR of active pharmaceutical ingredients". United States. doi:10.1039/c6cp04353d. https://www.osti.gov/servlets/purl/1335033.
@article{osti_1335033,
title = {35Cl dynamic nuclear polarization solid-state NMR of active pharmaceutical ingredients},
author = {Hirsh, David A. and Rossini, Aaron J. and Emsley, Lyndon and Schurko, Robert W.},
abstractNote = {In this paper, we show how to obtain efficient dynamic nuclear polarization (DNP) enhanced 35Cl 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 and 1H–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 wideline 35Cl 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-enhanced 35Cl 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-enhanced 1H–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.},
doi = {10.1039/c6cp04353d},
journal = {Physical Chemistry Chemical Physics. PCCP (Print)},
number = 37,
volume = 18,
place = {United States},
year = 2016,
month = 8
}

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Cited by: 6works
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  • Here, we report that spatial (<1 nm) proximity between different molecules in solid bulk materials and, for the first time, different moieties on the surface of a catalyst, can be established without isotope enrichment by means of homonuclear CHHC solid-state nuclear magnetic resonance experiment. This 13C– 13C correlation measurement, which hitherto was not possible for natural-abundance solids, was enabled by the use of dynamic nuclear polarization. Importantly, it allows the study of long-range correlations in a variety of materials with high resolution.
  • Chemically Induced Dynamic Nuclear Polarization (CIDNP) is an efficient method of creating non-equilibrium polarization of nuclear spins by using chemical reactions, which have radical pairs as intermediates. The CIDNP effect originates from (i) electron spin-selective recombination of radical pairs and (ii) the dependence of the inter-system crossing rate in radical pairs on the state of magnetic nuclei. The CIDNP effect can be investigated by using Nuclear Magnetic Resonance (NMR) methods. The gain from CIDNP is then two-fold: it allows one to obtain considerable amplification of NMR signals; in addition, it provides a very useful tool for investigating elusive radicals andmore » radical pairs. While the mechanisms of the CIDNP effect in liquids are well established and understood, detailed analysis of solid-state CIDNP mechanisms still remains challenging; likewise a common theoretical frame for the description of CIDNP in both solids and liquids is missing. Difficulties in understanding the spin dynamics that lead to the CIDNP effect in the solid-state case are caused by the anisotropy of spin interactions, which increase the complexity of spin evolution. In this work, we propose to analyze CIDNP in terms of level crossing phenomena, namely, to attribute features in the CIDNP magnetic field dependence to Level Crossings (LCs) and Level Anti-Crossings (LACs) in a radical pair. This approach allows one to describe liquid-state CIDNP; the same holds for the solid-state case where anisotropic interactions play a significant role in CIDNP formation. In solids, features arise predominantly from LACs, since in most cases anisotropic couplings result in perturbations, which turn LCs into LACs. We have interpreted the CIDNP mechanisms in terms of the LC/LAC concept. This consideration allows one to find analytical expressions for a wide magnetic field range, where several different mechanisms are operative; furthermore, the LAC description gives a way to determine CIDNP sign rules. Thus, LCs/LACs provide a consistent description of CIDNP in both liquids and solids with the prospect of exploiting it for the analysis of short-lived radicals and for optimizing the polarization level.« less
  • We present here a novel application of solid-state nuclear magnetic resonance (SSNMR) to bacterial photosynthesis: we have observed photochemically induced dynamic nuclear polarization (photo-CIDNP) in the {sup 15}N-SSNMR-magic-angle spinning (MAS) spectra of reaction centers from photosynthetic bacteria. In nonspecifically {sup 15}N-labeled reaction centers, when forward electron transfer was blocked either by removal (Q-deep) or prereduction (Q-red) of the quinone acceptor, strongly emissive {sup 15}N signals were observed. We attribute these signals to the tetrapyrrole nitrogen of the ground state of the special pair P. CIDNP is a well-known effect in solution NMR and is utilized for studying the mechanisms ofmore » photochemical reactions. In contrast to the large nuymber of mechanistic studies by solution-state CIDNP, to our knowledge, this is the first observation of S-T{sub 0}CIDNP in the solid state and is certainly the first application for studying membrane biophysics. 19 refs., 1 fig.« less