Solid-State NMR Analysis of a Complex Crystalline Phase of Ronacaleret Hydrochloride

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. 1H 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. 19F and 13C assignments
for the Z′ = 2 structure are obtained using
DFT calculations, 19F homonuclear dipolar correlation,
and 13C–19F heteronuclear dipolar correlation
experiments. 35Cl 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 1H–13C, 1H–15N, 1H–19F, 13C–19F, and 1H–35Cl 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.