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Structure and physicochemical characterization of a naproxen – picolinamide cocrystal

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ABSTRACT

Naproxen (NPX) is a nonsteroidal anti-inflammatory drug with pain- and fever-relieving properties, currently marketed in the sodium salt form to overcome solubility problems; however, alternative solutions for improving its solubility across all pH values are desirable. NPX is suitable for cocrystal formation, with hydrogen-bonding possibilities via the COOH group. The crystal structure is presented of a 1:1 cocrystal of NPX with picolinamide as a coformer [systematic name: (S)-2-(6-meth­oxy­naphthalen-2-yl)propanoic acid–pyridine-2-carbox­amide (1/1), C14H14O3·C6H6N2O]. The pharmaceutically relevant physical properties were investigated and the intrinsic dissolution rate was found to be essentially the same as that of commercial naproxen. An NMR crystallography approach was used to investigate the H-atom positions in the two crystallographically unique COOH–CONH hydrogen-bonded dimers. 1H solid-state NMR distinguished the two carboxyl protons, despite the very similar crystallographic environments. The nature of the hydrogen bonding was confirmed by solid-state NMR and density functional theory calculations.

No MeSH data available.


13C CP/MAS spectra of (a) pure NPX, (b) a physical mixture of NPX and PA, and (c) the NPX–PA cocrystal acquired at a 13C frequency of 100.56 MHz. Peaks marked with an asterix are spinning sidebands and the dashed blue lines are guides for the eye to show new or shifted peaks in the cocrystal.
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fig4: 13C CP/MAS spectra of (a) pure NPX, (b) a physical mixture of NPX and PA, and (c) the NPX–PA cocrystal acquired at a 13C frequency of 100.56 MHz. Peaks marked with an asterix are spinning sidebands and the dashed blue lines are guides for the eye to show new or shifted peaks in the cocrystal.

Mentions: Comparison of the 13C spectra of the pure components with that of the grinding product confirms the formation of a cocrystal (Fig. 4 ▸). The physical mixture and pure NPX show identical spectra, consistent with a lack of inter­action between components. Peaks from PA are not observed because the pure PA coformer has a long 1H T1 relaxation time compared to the recycle delay of 5 s. The spectrum of the NPX–PA cocrystal is distinctly different. Firstly, some of the resonances arising from NPX have shifted relative to the pure NPX spectrum, e.g. the C9/C46 peak. The deshielding observed for the NPX COOH sites, i.e. C2 and C37, is consistent with the formation of hydrogen bonds (Asakawa et al., 1992 ▸). Secondly, signals are now observed from PA carbon sites as a result of the intimate association of PA and NPX, which shortens the 1H T1 relaxation time of the PA resonances. The doubling of most signals is consistent with the presence of two crystallographically non-equivalent mol­ecules of NPX and PA in the asymmetric unit determined from single-crystal X-ray diffraction. Key peaks are assigned in Fig. 5 ▸, and the full assignment is given in Fig. S5 and Table S3 in the Supporting information. The spectral assignments were aided by a 13C spectrum with the nonquaternary carbon peaks suppressed (Fig. S4 in the Supporting information) and 2D 1H–13C heteronuclear correlation (HETCOR) experiments (Figs. S5 and S6 in the Supporting information), as well as CASTEP-calculated shieldings (Figs. S8 and S9 in the Supporting information), discussed below. A direct-excitation 13C experiment (not shown) with a short recycle delay of 0.5 s showed that the only obviously dynamic sites are the methyl groups.


Structure and physicochemical characterization of a naproxen – picolinamide cocrystal
13C CP/MAS spectra of (a) pure NPX, (b) a physical mixture of NPX and PA, and (c) the NPX–PA cocrystal acquired at a 13C frequency of 100.56 MHz. Peaks marked with an asterix are spinning sidebands and the dashed blue lines are guides for the eye to show new or shifted peaks in the cocrystal.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5391861&req=5

fig4: 13C CP/MAS spectra of (a) pure NPX, (b) a physical mixture of NPX and PA, and (c) the NPX–PA cocrystal acquired at a 13C frequency of 100.56 MHz. Peaks marked with an asterix are spinning sidebands and the dashed blue lines are guides for the eye to show new or shifted peaks in the cocrystal.
Mentions: Comparison of the 13C spectra of the pure components with that of the grinding product confirms the formation of a cocrystal (Fig. 4 ▸). The physical mixture and pure NPX show identical spectra, consistent with a lack of inter­action between components. Peaks from PA are not observed because the pure PA coformer has a long 1H T1 relaxation time compared to the recycle delay of 5 s. The spectrum of the NPX–PA cocrystal is distinctly different. Firstly, some of the resonances arising from NPX have shifted relative to the pure NPX spectrum, e.g. the C9/C46 peak. The deshielding observed for the NPX COOH sites, i.e. C2 and C37, is consistent with the formation of hydrogen bonds (Asakawa et al., 1992 ▸). Secondly, signals are now observed from PA carbon sites as a result of the intimate association of PA and NPX, which shortens the 1H T1 relaxation time of the PA resonances. The doubling of most signals is consistent with the presence of two crystallographically non-equivalent mol­ecules of NPX and PA in the asymmetric unit determined from single-crystal X-ray diffraction. Key peaks are assigned in Fig. 5 ▸, and the full assignment is given in Fig. S5 and Table S3 in the Supporting information. The spectral assignments were aided by a 13C spectrum with the nonquaternary carbon peaks suppressed (Fig. S4 in the Supporting information) and 2D 1H–13C heteronuclear correlation (HETCOR) experiments (Figs. S5 and S6 in the Supporting information), as well as CASTEP-calculated shieldings (Figs. S8 and S9 in the Supporting information), discussed below. A direct-excitation 13C experiment (not shown) with a short recycle delay of 0.5 s showed that the only obviously dynamic sites are the methyl groups.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Naproxen (NPX) is a nonsteroidal anti-inflammatory drug with pain- and fever-relieving properties, currently marketed in the sodium salt form to overcome solubility problems; however, alternative solutions for improving its solubility across all pH values are desirable. NPX is suitable for cocrystal formation, with hydrogen-bonding possibilities via the COOH group. The crystal structure is presented of a 1:1 cocrystal of NPX with picolinamide as a coformer [systematic name: (S)-2-(6-meth­oxy­naphthalen-2-yl)propanoic acid–pyridine-2-carbox­amide (1/1), C14H14O3·C6H6N2O]. The pharmaceutically relevant physical properties were investigated and the intrinsic dissolution rate was found to be essentially the same as that of commercial naproxen. An NMR crystallography approach was used to investigate the H-atom positions in the two crystallographically unique COOH–CONH hydrogen-bonded dimers. 1H solid-state NMR distinguished the two carboxyl protons, despite the very similar crystallographic environments. The nature of the hydrogen bonding was confirmed by solid-state NMR and density functional theory calculations.

No MeSH data available.