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 13C peaks for naproxen and the cocrystal were performed using dipolar-insensitive nuclei enhanced by polarization transfer and 1H–13C cross-polarization (CP)–heteronuclear correlation (HETCOR) NMR measurements. The 13C chemical shift revealed that two naproxen molecules and one nicotinamide molecule existed in the asymmetric unit of the cocrystal. The 1H 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 1H–13C 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. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association.