Conformational analysis by solid-state NMR and its application to restrained structure determination from powder diffraction data

Abstract

Solid-state NMR is used to dramatically improve the efficiency and reliability of molecular crystal structure determination from X-ray powder diffraction data.

Crystallography and NMR: An Overview

“…39 Dipolar coupling results can form even more powerful constraints on crystal structures. 40 The ultimate goal may be to incorporate such computations into procedures to determine crystal structures by the simultaneous refinement of NMR and diffraction data.…”

Enantiotropically-related polymorphs of {4-(4-chloro-3-fluorophenyl)-2-[4-(methyloxy)phenyl]-1,3-thiazol-5-yl} acetic acid: Crystal structures and multinuclear solid-state NMR

“…6,7 Recently, various combinations of SSNMR methods with PXRD solution approaches have been explored. 8,9 If these two approaches can be successfully combined and applied routinely and robustly to small-molecule drugs, an avenue toward the crystal structures of many more polymorphs would be available, and the understanding of the structural basis behind polymorph stability relationships could be enhanced though the structures themselves or through the application of the latest computational tools.…”

“…These two complementary NMR approaches are not usually combined in the same study. [7][8][9] The role of hydrogen-bonding and p-stacking in the structures is also carefully considered. This work also seeks to understand the molecular basis behind polymorphic stability of these polymorphs, while contributing to the practical question of how forms can be quickly assessed for development using structural analysis methods as early in the development process as possible (e.g., immediately after a polymorph, salt, co-crystal, or solvate is discovered).…”

“…More quantitative approaches using 19 F- 13 C dipolar distance measurements are possible, 9,25 but generally require much longer experiments, and were unnecessary in the present case given the similarity in packing between the polymorphs.…”

Structure determination from powder diffraction data

“…For example, if the complete molecular conformation can be determined in advance of the diffraction experiment, global optimization is reduced to a problem of determining the position and orientation of a rigid molecule. Middleton and colleagues (Middleton et al, 2002) The potential energy (correlated integrated intensities 2 ) and total energy (kinetic energy plus potential energy) evaluated over a single MD trajectory during the crystal-structure solution of capsaicin. The initial total energy is shown as a dotted line in order to highlight the total energy fluctuations arising from the finite MD step size.…”