Efficient Strategy for Determining the Atomic-Resolution Structure of Micro- and Nanocrystalline Solids within Polymeric Microbeads: Domain-Edited NMR Crystallography

Abstract

Precise structural analysis of multiphase polymeric nanocomposites remains a challenge even in the presence of high-quality X-ray diffraction data. This contribution thus addresses our attempt to formulate a combined analytical strategy for obtaining the atomic-resolution structure of multicomponent polymeric solids with complex nanodomain architecture. In this strategy, through the application of T 1-filtered solid-state NMR spectroscopy, the individual components are successively distinguished and selected, and the corresponding 1H, 13C, and 15N isotropic chemical shifts are explicitly assigned. Thereafter, using an automated protocol allowing for processing and statistical analysis of large data sets, the experimentally determined NMR parameters are systematically compared with those DFT-calculated for the representative set of crystal structure predictions. Particular attention is devoted to the analysis of NMR parameters of hydrogen-bonded protons which are responsible for molecular packing. As a result of this search, the structures of micro- and nanosized crystallites dispersed in the polymeric matrix are determined and independently verified by the measurements of through-space dipolar couplings. The potential of this strategy is demonstrated on injectable polyanhydride microbeads consisting of a mixture of microcrystalline decitabine and nanocrystalline sebacic acid, both incorporated in the semicrystalline polymeric matrix of poly­(sebacic acid). Through the synergistic interplay between the measurements, calculations, and the statistical analysis, we have developed an integrated approach providing structural information that is challenging to elucidate using conventional diffraction approaches. This combination of experimental and theoretical approaches enables one to determine the structural arrangements of molecules in situations which are not tractable by conventional spectroscopic techniques.

NMR Crystallography of the Polymorphs of Metergoline

“…Additionally, some of its notable applications were most recently discussed by Brown et al [7] and by Emsley et al [8]. Our group successfully employed NMR crystallography in the structural elucidation/refinement of framework materials [9], bioactive compounds [10], and drugs [11][12][13]. Here, further extensions of the NMR crystallography methodology are described, together with results that were obtained for the two known crystal modifications (polymorphs) of the active pharmaceutical ingredient (API) metergoline, which is an established serotonin antagonist [14].…”

“…This polymorph was previously investigated [16] by SSNMR measurements and by various density-functional theory (DFT)-based approaches to the description of structural and NMR-spectroscopic parameters. Importantly, the full assignment of the 1 H- 13 C heteronuclear correlation (HETCOR) signals was achieved. Both plane-wave (PW) DFT methods with periodic boundary conditions being imposed to treat the structure as an infinite crystal and the cluster model [17] were applied.…”

“…This group proposed a strategy for selecting the correct candidate structure(s) from a set of crystal structure predictions (CSPs) that were based on statistical evaluation of the level of agreement between theoretical and experimental values of the { 1 H, 13 C} isotropic chemical shifts [12]. Most recently, this approach was expanded to include the 15 N chemical shifts as well, and the selection procedure was partially automated [13].…”

“…This group proposed a strategy for selecting the correct candidate structure(s) from a set of crystal structure predictions (CSPs) that were based on statistical evaluation of the level of agreement between theoretical and experimental values of the { 1 H, 13 C} isotropic chemical shifts [12]. Most recently, this approach was expanded to include the 15 N chemical shifts as well, and the selection procedure was partially automated [13]. In this work, measurements and PW DFT calculations of the principal elements of the 13 C chemical shift tensors (CSTs) were carried out for polymorph I, and the data were included (together with the explicitly assigned 13 C and 1 H isotropic chemical shifts) in the process of discriminating between structural models in order to exclude incorrect CSPs.…”

“…Most recently, this approach was expanded to include the 15 N chemical shifts as well, and the selection procedure was partially automated [13]. In this work, measurements and PW DFT calculations of the principal elements of the 13 C chemical shift tensors (CSTs) were carried out for polymorph I, and the data were included (together with the explicitly assigned 13 C and 1 H isotropic chemical shifts) in the process of discriminating between structural models in order to exclude incorrect CSPs. This enhancement represents the next step in increasing the reliability of NMR crystallography for the verification of crystal structures.…”