Structure and physicochemical characterization of a naproxen-picolinamide cocrystal.

Hannah E Kerr,Ivana Radosavljevic Evans,Kuthuru Suresh,Lorna K Softley,Paul Hodgkinson

doi:10.1107/s2053229616011980

Hannah E Kerr, Ivana Radosavljevic Evans + Show 3 more

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https://doi.org/10.1107/s2053229616011980

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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.

Highlights

Naproxen (NPX, Scheme 1), or (S)-2-(6-methoxynaphthalen2-yl)propanoic acid, is a nonsteroidal anti-inflammatory drug with pain- and fever-relieving properties, commonly used in the treatment of arthritis, dysmenorrhea and acute gout
We report here the growth of NPX–PA single crystals, the structure determination by single-crystal X-ray diffraction, the preparation of a pure polycrystalline sample of this cocrystal and the determination of its pharmaceutically-relevant properties
NPX–PA crystallizes in the space group P21 with four molecules in the asymmetric unit [two active pharmaceutical ingredient (API) and two conformer molecules]

Summary

Introduction

Naproxen (NPX, Scheme 1), or (S)-2-(6-methoxynaphthalen2-yl)propanoic acid, is a nonsteroidal anti-inflammatory drug with pain- and fever-relieving properties, commonly used in the treatment of arthritis, dysmenorrhea and acute gout. NPX is a weak acid (DrugBank, accessed July 2016; Wishart et al, 2006), with a pKa value of 4.2, leaving it un-ionized in gastrointestinal fluids. It is formally classified as a low-solubility high-permeability drug (Takagi et al, 2006), but its solubility is highly dependent on the pH of the surrounding environment. In environments with higher pH, such as in the membranes surrounding the cells, NPX becomes ionized, with the charged COOÀ group forming more favourable interactions with water, enhancing dissolution. To overcome the solubility problems, NPX is currently marketed in a salt form, i.e. naproxen sodium; alternative solutions for improving the solubility of NPX across all pH values are desirable

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