title: Physicochemical characterization and structural evaluation of a specific 2:1 cocrystal of naproxen-nicotinamide.
abstract: Physicochemical characterization and structural evaluation of a 2:1 naproxen-nicotinamide cocrystal were performed. The 2:1 cocrystal showed rapid naproxen dissolution and less water vapor adsorption, indicating better pharmaceutical properties of naproxen. The unique 2:1 cocrystal formation was evaluated by solid-state nuclear magnetic resonance (NMR). The assignments of all H and (13) C peaks for naproxen and the cocrystal were performed using dipolar-insensitive nuclei enhanced by polarization transfer and (1) H-(13) C cross-polarization (CP)-heteronuclear correlation (HETCOR) NMR measurements. The (13) C chemical shift revealed that two naproxen molecules and one nicotinamide molecule existed in the asymmetric unit of the cocrystal. The (1) H chemical shifts indicated that the carboxylic group of the naproxen in the cocrystal was nonionized, and the CH-π interaction between naproxens was very strong. From the (1) H-(13) C CP-HETCOR NMR spectrum with contact time of 5 ms, two different synthons, carboxylic acid-amide and carboxylic acid-pyridine ring, were found between naproxen and nicotinamide. Single-crystal X-ray analysis, which supported the solid-state NMR results, clarified the geometry and intermolecular interactions in more detail. The structure is unique among pharmaceutical cocrystals because each carboxyl group of the two naproxens formed different intermolecular synthons.
authors.affiliation: Innovative Drug Discovery Research Laboratories, Shionogi & Company, Ltd., Toyonaka-shi, Osaka 561-0825, Japan. shigeru.andou@shionogi.co.jp
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ando
authors.forename: Junko
authors.initials: J
authors.lastname: Kikuchi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fujimura
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ida
authors.forename: Kenjirou
authors.initials: K
authors.lastname: Higashi
authors.forename: Kunikazu
authors.initials: K
authors.lastname: Moribe
authors.forename: Keiji
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000327:Adsorption; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D018360:Crystallography, X-Ray; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009288:Naproxen / Q000737:chemistry*; D009536:Niacinamide / Q000737:chemistry*; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D014835:Volatilization; D014867:Water / Q000737:chemistry; D017155:Wettability
chemical_list: D014867:Water; D009536:Niacinamide; D009288:Naproxen