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Title: Characterization of Pharmaceutical Cocrystals and Salts by Dynamic Nuclear Polarization-Enhanced Solid-State NMR Spectroscopy

Abstract

Multicomponent solids such as cocrystals have emerged as a way to control and engineer the stability, solubility and manufacturability of solid active pharmaceutical ingredients (APIs). Cocrystals are typically formed by solution- or solid-phase reactions of APIs with suitable cocrystal coformers, which are often weak acids. One key structural question about a given multicomponent solid is whether it should be classified as a salt, where the basic API is protonated by the acid, or as a cocrystal, where the API and coformer remain neutral and engage in hydrogen bonding interactions. It has previously been demonstrated that solid-state NMR spectroscopy is a powerful probe of structure in cocrystals and salts of APIs, however, the poor sensitivity of solid-state NMR spectroscopy usually restricts the types of experiments that can be performed. Here relayed dynamic nuclear polarization (DNP) was applied to reduce solid-state NMR experiments by one to two orders of magnitude for salts and cocrystals of a complex API. The large sensitivity gains from DNP facilitates rapid acquisition of natural isotopic abundance 13C and 15N solid-state NMR spectra. Critically, DNP enables double resonance 1H-15N solid-state NMR experiments such as 2D 1H-15N HETCOR, 1H-15N CP-build up, 15N{1H} J-resolved/attached proton tests, 1H-15N DIPSHIFT and 1H-15Nmore » PRESTO. The latter two experiments allow 1H-15N dipolar coupling constants and H-N bond lengths to be accurately measured, providing an unambiguous assignment of nitrogen protonation state and definitive classification of the multi-component solids as cocrystals or salts. In conclusion, these types of measurements should also be extremely useful in the context of polymorph discrimination, NMR crystallography structure determination and for probing hydrogen bonding in a variety of organic materials.« less

Authors:
 [1];  [1];  [2];  [2];  [2];  [2];  [2];  [1]
  1. Iowa State Univ., Ames, IA (United States). Dept. of Chemistry; Ames Lab., Ames, IA (United States)
  2. Genentech, Inc., San Francisco, CA (United States)
Publication Date:
Research Org.:
Ames Laboratory (AMES), Ames, IA (United States)
Sponsoring Org.:
USDOE; National Science Foundation (NSF)
OSTI Identifier:
1422770
Report Number(s):
IS-J-9577
Journal ID: ISSN 1528-7483
Grant/Contract Number:  
AC02-07CH11358; 1709972
Resource Type:
Accepted Manuscript
Journal Name:
Crystal Growth and Design
Additional Journal Information:
Journal Volume: 18; Journal Issue: 4; Journal ID: ISSN 1528-7483
Publisher:
American Chemical Society
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 36 MATERIALS SCIENCE

Citation Formats

Zhao, Li, Hanrahan, Michael P., Chakravarty, Paroma, Dipasquale, Antonio G., Sirois, Lauren Elizabeth, Nagapudi, Karthik, Lubach, Joseph W., and Rossini, Aaron J. Characterization of Pharmaceutical Cocrystals and Salts by Dynamic Nuclear Polarization-Enhanced Solid-State NMR Spectroscopy. United States: N. p., 2018. Web. doi:10.1021/acs.cgd.8b00203.
Zhao, Li, Hanrahan, Michael P., Chakravarty, Paroma, Dipasquale, Antonio G., Sirois, Lauren Elizabeth, Nagapudi, Karthik, Lubach, Joseph W., & Rossini, Aaron J. Characterization of Pharmaceutical Cocrystals and Salts by Dynamic Nuclear Polarization-Enhanced Solid-State NMR Spectroscopy. United States. https://doi.org/10.1021/acs.cgd.8b00203
Zhao, Li, Hanrahan, Michael P., Chakravarty, Paroma, Dipasquale, Antonio G., Sirois, Lauren Elizabeth, Nagapudi, Karthik, Lubach, Joseph W., and Rossini, Aaron J. Thu . "Characterization of Pharmaceutical Cocrystals and Salts by Dynamic Nuclear Polarization-Enhanced Solid-State NMR Spectroscopy". United States. https://doi.org/10.1021/acs.cgd.8b00203. https://www.osti.gov/servlets/purl/1422770.
@article{osti_1422770,
title = {Characterization of Pharmaceutical Cocrystals and Salts by Dynamic Nuclear Polarization-Enhanced Solid-State NMR Spectroscopy},
author = {Zhao, Li and Hanrahan, Michael P. and Chakravarty, Paroma and Dipasquale, Antonio G. and Sirois, Lauren Elizabeth and Nagapudi, Karthik and Lubach, Joseph W. and Rossini, Aaron J.},
abstractNote = {Multicomponent solids such as cocrystals have emerged as a way to control and engineer the stability, solubility and manufacturability of solid active pharmaceutical ingredients (APIs). Cocrystals are typically formed by solution- or solid-phase reactions of APIs with suitable cocrystal coformers, which are often weak acids. One key structural question about a given multicomponent solid is whether it should be classified as a salt, where the basic API is protonated by the acid, or as a cocrystal, where the API and coformer remain neutral and engage in hydrogen bonding interactions. It has previously been demonstrated that solid-state NMR spectroscopy is a powerful probe of structure in cocrystals and salts of APIs, however, the poor sensitivity of solid-state NMR spectroscopy usually restricts the types of experiments that can be performed. Here relayed dynamic nuclear polarization (DNP) was applied to reduce solid-state NMR experiments by one to two orders of magnitude for salts and cocrystals of a complex API. The large sensitivity gains from DNP facilitates rapid acquisition of natural isotopic abundance 13C and 15N solid-state NMR spectra. Critically, DNP enables double resonance 1H-15N solid-state NMR experiments such as 2D 1H-15N HETCOR, 1H-15N CP-build up, 15N{1H} J-resolved/attached proton tests, 1H-15N DIPSHIFT and 1H-15N PRESTO. The latter two experiments allow 1H-15N dipolar coupling constants and H-N bond lengths to be accurately measured, providing an unambiguous assignment of nitrogen protonation state and definitive classification of the multi-component solids as cocrystals or salts. In conclusion, these types of measurements should also be extremely useful in the context of polymorph discrimination, NMR crystallography structure determination and for probing hydrogen bonding in a variety of organic materials.},
doi = {10.1021/acs.cgd.8b00203},
journal = {Crystal Growth and Design},
number = 4,
volume = 18,
place = {United States},
year = {Thu Feb 15 00:00:00 EST 2018},
month = {Thu Feb 15 00:00:00 EST 2018}
}

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Figures / Tables:

Scheme 1 Scheme 1: Molecular structures of the API, compound A ((1R,5S,6S)-3-(2,5-difluoro-4- {[(3S,6R)-3-methyl-1,1-dioxido-6-phenyl-1,2-thiazinan-2-yl]methyl}phenyl)-6-(4H-1,2,4- triazol-4-yl)-3-azabicyclo[3.1.0]hexane) and the coformers, phosphoric acid (1), fumaric acid (2) and tosylic acid (3), discussed in this study. The nitrogen atoms of A are labelled as N2, N24, N31, N33 and N34.

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Facile measurement of 1H–15N residual dipolar couplings in larger perdeuterated proteins
journal, August 2010


Indirectly detected heteronuclear correlation solid-state NMR spectroscopy of naturally abundant 15N nuclei
journal, February 2014

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Enhanced sensitivity in high-resolution 1H solid-state NMR spectroscopy with DUMBO dipolar decoupling under ultra-fast MAS
journal, February 2009


Coupling Amplification in 2D MAS NMR and Its Application to Torsion Angle Determination in Peptides
journal, November 1997

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Heteronuclear polarization transfer by symmetry-based recoupling sequences in solid-state NMR
journal, September 2004

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Neutron diffraction study of L-histidine hydrochloride monohydrate
journal, March 1977

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Nuclear Magnetic Resonance Saturation and Rotary Saturation in Solids
journal, June 1955


Nuclear-Magnetic-Resonance Line Narrowing by a Rotating rf Field
journal, November 1965


Natural Abundance 17 O DNP Two-Dimensional and Surface-Enhanced NMR Spectroscopy
journal, June 2015

  • Perras, Frédéric A.; Kobayashi, Takeshi; Pruski, Marek
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Above-room-temperature ferroelectricity in a single-component molecular crystal
journal, February 2010

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Solid-state dynamic nuclear polarization at 263 GHz: spectrometer design and experimental results
journal, January 2010

  • Rosay, Melanie; Tometich, Leo; Pawsey, Shane
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NMR nomenclature. Nuclear spin properties and conventions for chemical shifts(IUPAC Recommendations 2001)
journal, January 2001

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  • Pure and Applied Chemistry, Vol. 73, Issue 11
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Magic-angle spinning and polarization transfer in proton-enhanced NMR
journal, October 1977


Variable-Amplitude Cross-Polarization MAS NMR
journal, October 1993

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An Improved Broadband Decoupling Sequence for Liquid Crystals and Solids
journal, January 2000

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  • Journal of Magnetic Resonance, Vol. 142, Issue 1
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Two-dimensional heteronuclear chemical shift correlation spectroscopy in rotating solids
journal, May 1984

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SIMPSON: A General Simulation Program for Solid-State NMR Spectroscopy
journal, December 2000

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Optimal control in NMR spectroscopy: Numerical implementation in SIMPSON
journal, April 2009

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  • Journal of Magnetic Resonance, Vol. 197, Issue 2
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Computer-intensive simulation of solid-state NMR experiments using SIMPSON
journal, September 2014

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  • Journal of Magnetic Resonance, Vol. 246
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First principles methods using CASTEP
journal, January 2005

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Generalized Gradient Approximation Made Simple
journal, October 1996

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Calculation of NMR chemical shifts for extended systems using ultrasoft pseudopotentials
journal, July 2007


Semiempirical GGA-type density functional constructed with a long-range dispersion correction
journal, January 2006

  • Grimme, Stefan
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All-electron magnetic response with pseudopotentials: NMR chemical shifts
journal, May 2001


Benchmark fragment-based 1 H, 13 C, 15 N and 17 O chemical shift predictions in molecular crystals
journal, January 2016

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Works referencing / citing this record:

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Understanding hydrogen-bonding structures of molecular crystals via electron and NMR nanocrystallography
journal, August 2019

  • Guzmán-Afonso, Candelaria; Hong, You-lee; Colaux, Henri
  • Nature Communications, Vol. 10, Issue 1
  • DOI: 10.1038/s41467-019-11469-2

Co-crystals, Salts or Mixtures of Both? The Case of Tenofovir Alafenamide Fumarates
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  • Viger‐Gravel, Jasmine; Avalos, Claudia E.; Kubicki, Dominik J.
  • Angewandte Chemie, Vol. 131, Issue 22
  • DOI: 10.1002/ange.201814416

Large-scale ab initio simulations of MAS DNP enhancements using a Monte Carlo optimization strategy
journal, October 2018

  • Perras, Frédéric A.; Pruski, Marek
  • The Journal of Chemical Physics, Vol. 149, Issue 15
  • DOI: 10.1063/1.5042651

Spectroscopic (FT-IR, FT-Raman, and 13 C SS-NMR) and quantum chemical investigations to provide structural insights into nitrofurantoin–4-hydroxybenzoic acid cocrystals
journal, January 2019

  • Shukla, Anuradha; Khan, Eram; Alsirawan, MHD. Bashir
  • New Journal of Chemistry, Vol. 43, Issue 18
  • DOI: 10.1039/c8nj05946b

19 F Magic Angle Spinning Dynamic Nuclear Polarization Enhanced NMR Spectroscopy
journal, May 2019

  • Viger‐Gravel, Jasmine; Avalos, Claudia E.; Kubicki, Dominik J.
  • Angewandte Chemie International Edition, Vol. 58, Issue 22
  • DOI: 10.1002/anie.201814416

Understanding hydrogen-bonding structures of molecular crystals via electron and NMR nanocrystallography
journal, August 2019

  • Guzmán-Afonso, Candelaria; Hong, You-lee; Colaux, Henri
  • Nature Communications, Vol. 10, Issue 1
  • DOI: 10.1038/s41467-019-11469-2

Figures/Tables have been extracted from DOE-funded journal article accepted manuscripts.