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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 Lab., 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. 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., & 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 = {2018},
month = {2}
}

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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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Nuclear-Magnetic-Resonance Line Narrowing by a Rotating rf Field
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Natural Abundance 17 O DNP Two-Dimensional and Surface-Enhanced NMR Spectroscopy
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Magic-angle spinning and polarization transfer in proton-enhanced NMR
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Calculation of NMR chemical shifts for extended systems using ultrasoft pseudopotentials
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    journal, October 2018

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

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