title: Structural basis for the transformation pathways of the sodium naproxen anhydrate-hydrate system.
abstract: Crystal structures are presented for two dihydrate polymorphs (DH-I and DH-II) of the non-steroidal anti-inflammatory drug sodium (S)-naproxen. The structure of DH-I is determined from twinned single crystals obtained by solution crystallization. DH-II is obtained by solid-state routes, and its structure is derived using powder X-ray diffraction, solid-state (13)C and (23)Na MAS NMR, and molecular modelling. The validity of both structures is supported by dispersion-corrected density functional theory (DFT-D) calculations. The structures of DH-I and DH-II, and in particular their relationships to the monohydrate (MH) and anhydrate (AH) structures, provide a basis to rationalize the observed transformation pathways in the sodium (S)-naproxen anhydrate-hydrate system. All structures contain Na(+)/carboxylate/H2O sections, alternating with sections containing the naproxen molecules. The structure of DH-I is essentially identical to MH in the naproxen region, containing face-to-face arrangements of the naphthalene rings, whereas the structure of DH-II is comparable to AH in the naproxen region, containing edge-to-face arrangements of the naphthalene rings. This structural similarity permits topotactic transformation between AH and DH-II, and between MH and DH-I, but requires re-organization of the naproxen molecules for transformation between any other pair of structures. The topotactic pathways dominate at room temperature or below, while the non-topotactic pathways become active at higher temperatures. Thermochemical data for the dehydration processes are rationalized in the light of this new structural information.
authors.affiliation: Department of Pharmacy, University of Copenhagen , Universitetsparken 2, Copenhagen DK-2100, Denmark.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Bond
authors.affiliation: Department of Pharmacy, University of Copenhagen , Universitetsparken 2, Copenhagen DK-2100, Denmark.
authors.forename: Claus
authors.initials: C
authors.lastname: Cornett
authors.affiliation: Department of Food Science, University of Copenhagen , Rolighedsvej 30, Frederiksberg DK-1958, Denmark.
authors.forename: Flemming H
authors.initials: FH
authors.lastname: Larsen
authors.affiliation: Department of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark , Niels Bohrs Alle 1, Odense DK-5230, Denmark.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Qu
authors.affiliation: Department of Pharmacy, University of Copenhagen , Universitetsparken 2, Copenhagen DK-2100, Denmark.
authors.forename: Dhara
authors.initials: D
authors.lastname: Raijada
authors.affiliation: Department of Pharmacy, University of Copenhagen , Universitetsparken 2, Copenhagen DK-2100, Denmark.
authors.forename: Jukka
authors.initials: J
authors.lastname: Rantanen
keywords: DFT-D; X-ray diffraction; hydrate; pharmaceutical; solid-state NMR