title: Solid-state NMR analysis of a complex crystalline phase of ronacaleret hydrochloride.
abstract: A crystalline phase of the pharmaceutical compound ronacaleret hydrochloride is studied by solid-state nuclear magnetic resonance (SSNMR) spectroscopy and single-crystal X-ray diffraction. The crystal structure is determined to contain two independent cationic molecules and chloride anions in the asymmetric unit, which combine with the covalent structure of the molecule to yield complex SSNMR spectra. Experimental approaches based on dipolar correlation, chemical shift tensor analysis, and quadrupolar interaction analysis are employed to obtain detailed information about this phase. Density functional theory (DFT) calculations are used to predict chemical shielding and electric field gradient (EFG) parameters for comparison with experiment. (1)H SSNMR experiments performed at 16.4 T using magic-angle spinning (MAS) and homonuclear dipolar decoupling provide information about hydrogen bonding and molecular connectivity that can be related to the crystal structure. (19)F and (13)C assignments for the Z' = 2 structure are obtained using DFT calculations, (19)F homonuclear dipolar correlation, and (13)C-(19)F heteronuclear dipolar correlation experiments. (35)Cl MAS experiments at 16.4 T observe two chlorine sites that are assigned using calculated chemical shielding and EFG parameters. SSNMR dipolar correlation experiments are used to extract (1)H-(13)C, (1)H-(15)N, (1)H-(19)F, (13)C-(19)F, and (1)H-(35)Cl through-space connectivity information for many positions of interest. The results allow for the evaluation of the performance of a suite of SSNMR experiments and computational approaches as applied to a complex but typical pharmaceutical solid phase.
authors.affiliation: Product Development, GlaxoSmithKline plc. 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Frederick G
authors.initials: FG
authors.lastname: Vogt
authors.forename: Glenn R
authors.initials: GR
authors.lastname: Williams
authors.forename: Mark
authors.initials: M
authors.lastname: Strohmeier
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Johnson
authors.forename: Royston C B
authors.initials: RC
authors.lastname: Copley
mesh_terms: D002712:Chlorides / Q000737:chemistry*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D007189:Indans / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008956:Models, Chemical; D010666:Phenylpropionates / Q000737:chemistry*; D011789:Quantum Theory; D014961:X-Ray Diffraction
chemical_list: D002712:Chlorides; D007189:Indans; D010666:Phenylpropionates; C561716:ronacaleret