Exploiting the Synergy of Powder X-ray Diffraction and Solid-State NMR Spectroscopy in Structure Determination of Organic Molecular Solids

Abstract

We report a strategy for structure determination of organic materials in which complete solid-state nuclear magnetic resonance (NMR) spectral data is utilized within the context of structure determination from powder X-ray diffraction (XRD) data. Following determination of the crystal structure from powder XRD data, first-principles density functional theory-based techniques within the GIPAW approach are exploited to calculate the solid-state NMR data for the structure, followed by careful scrutiny of the agreement with experimental solid-state NMR data. The successful application of this approach is demonstrated by structure determination of the 1:1 cocrystal of indomethacin and nicotinamide. The 1H and 13C chemical shifts calculated for the crystal structure determined from the powder XRD data are in excellent agreement with those measured experimentally, notably including the two-dimensional correlation of 1H and 13C chemical shifts for directly bonded 13C–1H moieties. The key feature of this combined approach is that the quality of the structure determined is assessed both against experimental powder XRD data and against experimental solid-state NMR data, thus providing a very robust validation of the veracity of the structure.

A13C solid-state NMR investigation of four cocrystals of caffeine and theophylline

“…Among the manifestations of this emerging area, one approach seeks to determine crystal structures de novo by combining isotropic NMR chemical shifts gathered from CP-MAS data with energy-based structure prediction and quantum chemical ab initio calculations of those chemical shifts to produce candidate structures of small organic molecules (Elena & Emsley, 2005;Salager et al, 2009). This approach, now well developed and demonstrated, has provided an alternative to Rietveld methods for determining crystal structures from polycrystalline powders, where in some instances it can be prohibitive to produce large enough single crystals for diffraction analysis (Pickard et al, 2007;Salager et al, 2010;Dudenko et al, 2013a;Brus et al, 2016;Watts et al, 2016). It is interesting to note that this approach uses only isotropic chemical shifts to eventually cull candidate structures.…”

Enhanced NMR Discrimination of Pharmaceutically Relevant Molecular Crystal Forms through Fragment-Based Ab Initio Chemical Shift Predictions

“…Chemical shift prediction is frequently used to confirm structures solved from powder X-ray diffraction, 4,6 to identify structures consistent with the experimental NMR spectrum, 7−16 to assign NMR spectra, 17−21 or even to help refine crystal structures. 21−30 Despite its sensitivity to local crystal packing, the changes in chemical shift across different polymorphs or crystallographic environments can be subtle.…”

An Investigation of Indomethacin–Nicotinamide Cocrystal Formation Induced by Thermal Stress in the Solid or Liquid State

“…Indomethacin is a typical poorly water‐soluble biopharmaceutical classification system class II drug . Several IMC cocrystals have been extensively investigated, in which nicotinamide (NIC) has been widely utilized as a coformer for IMC–NIC cocrystal formation because of its propensity to form intermolecular hydrogen bonds via its carboxamide and pyridine moieties . These IMC–NIC cocrystals have been prepared by several preparation methods, such as slurry crystallization, spray drying, solvent evaporation, and solvent‐assisted cogrinding.…”

“…25 Several IMC cocrystals have been extensively investigated, 26 nicotinamide (NIC) has been widely utilized as a coformer for IMC-NIC cocrystal formation because of its propensity to form intermolecular hydrogen bonds via its carboxamide and pyridine moieties. [27][28][29][30][31][32][33][34] These IMC-NIC cocrystals have been prepared by several preparation methods, such as slurry crystallization, spray drying, solvent evaporation, and solventassisted cogrinding. In the present study, IMC and NIC were selected as a drug candidate and coformer, respectively.…”