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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.


(a) Schematic showing the H atoms that were moved in tandem along the vector between the H atom and its acceptor atom to form Model 1 and Model 2. The white circles indicate the initial position of the H atoms from the XRD structure and the arrows indicate the direction of movement. (b) The energy of NPX–PA as a function of H-atom position. A fractional distance of 0 corresponds to the DFT-optimized XRD position, while a distance of 1 corresponds to the H atom being at the equivalent position on the other side of the hydrogen bond. Negative fractional distances correspond to movement towards the donor atom.
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fig6: (a) Schematic showing the H atoms that were moved in tandem along the vector between the H atom and its acceptor atom to form Model 1 and Model 2. The white circles indicate the initial position of the H atoms from the XRD structure and the arrows indicate the direction of movement. (b) The energy of NPX–PA as a function of H-atom position. A fractional distance of 0 corresponds to the DFT-optimized XRD position, while a distance of 1 corresponds to the H atom being at the equivalent position on the other side of the hydrogen bond. Negative fractional distances correspond to movement towards the donor atom.

Mentions: The 1H spectrum of NPX–PA acquired with fast MAS of 60 kHz (Fig. 5 ▸a), shows comparable resolution with that of the 2NPX–NA spectrum presented by Ando et al. (2012 ▸). It is likely that the chemical shifts of some of the protons are affected by inter­molecular ring-current effects due to the edge-to-face herringbone structure of NPX–PA, which is similar to that of pure NPX (Carignani et al., 2013 ▸). Whilst the broad linewidths of 1H SS–NMR can hinder the ability of SS–NMR to distinguish between protons in hydrogen bonds of the same type, there are many cocrystals/salts for which it is possible (Vogt et al., 2009 ▸; Gobetto et al., 2005 ▸; Sardo et al., 2015 ▸; Harris et al., 2010 ▸), including this case of NPX–PA. Not all 1H peaks could be assigned, but the peaks of the two protons involved in the synthon E dimers, i.e. H31 and H361, can be distinguished. Variable recycle delay experiments showed that the T1 relaxation of the hydrogen-bonded protons was significantly slower than that of other H atoms, and so a 20 s recycle delay was used to acquire the spectra shown in Fig. 6 ▸.


Structure and physicochemical characterization of a naproxen – picolinamide cocrystal
(a) Schematic showing the H atoms that were moved in tandem along the vector between the H atom and its acceptor atom to form Model 1 and Model 2. The white circles indicate the initial position of the H atoms from the XRD structure and the arrows indicate the direction of movement. (b) The energy of NPX–PA as a function of H-atom position. A fractional distance of 0 corresponds to the DFT-optimized XRD position, while a distance of 1 corresponds to the H atom being at the equivalent position on the other side of the hydrogen bond. Negative fractional distances correspond to movement towards the donor atom.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5391861&req=5

fig6: (a) Schematic showing the H atoms that were moved in tandem along the vector between the H atom and its acceptor atom to form Model 1 and Model 2. The white circles indicate the initial position of the H atoms from the XRD structure and the arrows indicate the direction of movement. (b) The energy of NPX–PA as a function of H-atom position. A fractional distance of 0 corresponds to the DFT-optimized XRD position, while a distance of 1 corresponds to the H atom being at the equivalent position on the other side of the hydrogen bond. Negative fractional distances correspond to movement towards the donor atom.
Mentions: The 1H spectrum of NPX–PA acquired with fast MAS of 60 kHz (Fig. 5 ▸a), shows comparable resolution with that of the 2NPX–NA spectrum presented by Ando et al. (2012 ▸). It is likely that the chemical shifts of some of the protons are affected by inter­molecular ring-current effects due to the edge-to-face herringbone structure of NPX–PA, which is similar to that of pure NPX (Carignani et al., 2013 ▸). Whilst the broad linewidths of 1H SS–NMR can hinder the ability of SS–NMR to distinguish between protons in hydrogen bonds of the same type, there are many cocrystals/salts for which it is possible (Vogt et al., 2009 ▸; Gobetto et al., 2005 ▸; Sardo et al., 2015 ▸; Harris et al., 2010 ▸), including this case of NPX–PA. Not all 1H peaks could be assigned, but the peaks of the two protons involved in the synthon E dimers, i.e. H31 and H361, can be distinguished. Variable recycle delay experiments showed that the T1 relaxation of the hydrogen-bonded protons was significantly slower than that of other H atoms, and so a 20 s recycle delay was used to acquire the spectra shown in Fig. 6 ▸.

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.