Isotope-Edited Infrared Spectroscopy for Efficient Discrimination between Pharmaceutical Salts and Cocrystals

Article abstract of DOI:10.1021/acs.molpharmaceut.7b00226

Isotope-edited infrared spectroscopy using carboxylic acids selectively labeled with ¹³C is proposed herein for the efficient discrimination of pharmaceutical salts and cocrystals, whereby proton-transfer probe vibrations are highlighted by isotope shifts. This new technique can accurately discriminate even a confusing salt from a cocrystal for the traditional method, highlighting the diagnostic peaks. In addition, the established technique also provided the OH in-plane bending vibrations corresponding to intermolecular hydrogen bonding at the carbonyl oxygens of the cocrystals. The technique will accelerate the discrimination, which is a critical process in cocrystal development.

Full text of DOI:10.1021/acs.molpharmaceut.7b00226

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Article
Isotope-edited Infrared Spectroscopy for Efficient
Discrimination between Pharmaceutical Salts and Cocrystals
Kentaro Iwata, Masatoshi Karashima, and Yukihiro Ikeda
Mol. Pharmaceutics, Just Accepted Manuscript • Publication Date (Web): 14 May 2017
Downloaded from http://pubs.acs.org on May 15, 2017
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Molecular Pharmaceutics
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Cover page
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Isotopeꢀedited Infrared Spectroscopy for Efficient
Discrimination between Pharmaceutical Salts and
Cocrystals
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Kentaro Iwata*, Masatoshi Karashima and Yukihiro Ikeda
Abstract: Isotopeꢀedited infrared spectroscopy using carboxylic acids selectively labeled with
13C is proposed herein for the efficient discrimination of pharmaceutical salts and cocrystals,
whereby protonꢀtransfer probe vibrations are highlighted by isotope shifts. This new technique
can accurately discriminate even a confusing salt from a cocrystal for the traditional method,
highlighting the diagnostic peaks. In addition, the established technique also provided the OH
inꢀplane bending vibrations corresponding to intermolecular hydrogen bonding at the carbonyl
oxygens of the cocrystals. The technique will accelerate the discrimination which is critical
process in cocrystal development.
*Analytical Development, Pharmaceutical Sciences, Takeda Pharmaceutical Company Limited,
2ꢀ26ꢀ1, MuraokaꢀHigashi, Fujisawa, Kanagawa, 251ꢀ8555, Japan, Tel No. +81ꢀ466ꢀ32ꢀ2855,
Fax No. +81ꢀ466ꢀ29ꢀ4432 Eꢀmail address: kentarou.iwata@takeda.com
Keywords: Salt, Cocrystal, Infrared Spectroscopy, Isotope shift and Carboxylic acid
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Molecular Pharmaceutics
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Isotopeꢀedited Infrared Spectroscopy for Efficient
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Kentaro Iwata*, Masatoshi Karashima and Yukihiro Ikeda
*Analytical Development, Pharmaceutical Sciences, Takeda Pharmaceutical Company Limited,
2ꢀ26ꢀ1, MuraokaꢀHigashi, Fujisawa, Kanagawa, 251ꢀ8555, Japan, Tel No. +81ꢀ466ꢀ32ꢀ2855,
Fax No. +81ꢀ466ꢀ29ꢀ4432, Eꢀmail address: kentarou.iwata@takeda.com
Abstract
Isotopeꢀedited infrared spectroscopy using carboxylic acids selectively labeled with 13C is
proposed herein for the efficient discrimination of pharmaceutical salts and cocrystals, whereby
protonꢀtransfer probe vibrations are highlighted by isotope shifts. This new technique can
accurately discriminate even a confusing salt from a cocrystal for the traditional method,
highlighting the diagnostic peaks. In addition, the established technique also provided the OH inꢀ
plane bending vibrations corresponding to intermolecular hydrogen bonding at the carbonyl
oxygens of the cocrystals. The technique will accelerate the discrimination which is critical
process in cocrystal development.
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Page 3 of 32
Molecular Pharmaceutics
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Introduction
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Cocrystal technology has drawn much attention for its application in the development of
neutral active pharmaceutical ingredients (APIs) and the improvement of their pharmaceutical
profiles1, 2. Pharmaceutical development of cocrystals has recently been highlighted in
publications by the U.S. Food and Drug Administration (FDA)3 and the European Medicines
Agency (EMA)4. These publications commonly require elucidating whether newly developed
API crystals exist as cocrystals, which are homogeneous multicomponent crystals where no
proton transfer occurs between the different components, unlike the case of salt crystals.
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Discrimination of cocrystals and salts is now an essential step to satisfy regulatory
requirements, and various techniques have been developed with this aim. While the ꢁpKa rule
(ꢁpKa = pKa(base) – pKa(acid)) is commonly used to predict the existence of proton transfer
between a given pair of components in a crystal, robust prediction by said rule is limited due to
the broad ꢁpKa boundaries5, 6 and the experimental difficulties in determining the accurate pKa of
poorly soluble APIs. For analytical discrimination, single crystal Xꢀray and neutron crystal
structure analysis are the most definitive and widely applicable techniques7, 8. However, these
methodologies are not always suitable due to limitations in the crystal size. Alternatively,
infrared (IR) spectroscopy5, 9, solidꢀstate nuclear magnetic resonance (ssNMR)10ꢀ13, and Xꢀray
photoelectron spectroscopy (XPS)14, 15 have been investigated as discrimination techniques.
Especially, midꢀIR spectroscopy is a common analytical method in pharmaceutical
development16, and the IR vibrations of various functional groups in coformers and APIs are
available for discrimination analysis9, 17ꢀ20. Furthermore, IR spectroscopy is an orthogonal
method for discrimination compared to ssNMR spectroscopy and XPS, since the spectra from
such techniques reflect the electron density of the target atoms, while the IR bands are related to
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