Solid-State NMR Analysis of Organic Cocrystals and Complexes

Abstract

Solid-state NMR (SSNMR) is capable of providing detailed structural information about organic and pharmaceutical cocrystals and complexes. SSNMR nondestructively analyzes small amounts of powdered material and generally yields data with higher information content than vibrational spectroscopy and powder X-ray diffraction methods. These advantages can be utilized in the analysis of pharmaceutical cocrystals, which are often initially produced using solvent drop grinding techniques that do not lend themselves to single crystal growth for X-ray diffraction studies. In this work, several molecular complexes and cocrystals are examined to understand the capabilities of the SSNMR techniques, particularly their ability to prove or disprove molecular association and observe structural features such as hydrogen bonding. Dipolar correlation experiments between spin pairs such as 1H−1H, 1H−13C, and 19F−13C are applied to study hydrogen bonding, intermolecular contacts, and spin diffusion to link individual molecules together in a crystal structure and quickly prove molecular association. Analysis of the principal components of chemical shift tensors is also utilized where relevant, as these are more sensitive to structural effects than the isotropic chemical shift alone. In addition, 1H T1 relaxation measurements are also demonstrated as a means to prove phase separation of components. On the basis of these results, a general experimental approach to cocrystal analysis by SSNMR is suggested.

Probing Intermolecular Crystal Packing in γ-Indomethacin by High-Resolution 1H Solid-State NMR Spectroscopy

“…1-3 While 13 C crosspolarisation (CP) MAS is an established workhouse technique, the power of high-resolution 1 H solidstate NMR experiments is starting to be recognised: 1 H chemical shifts have been determined from onedimensional fast-MAS spectra and two-dimensional 1 H- 13 C correlation spectra, [4][5][6][7][8][9][10][11][12][13] with H-H proximities being identified in two-dimensional 1 H-1 H DQ (double-quantum) MAS and DQ CRAMPS (combined rotation and multiple-pulse spectroscopy) spectra. [10][11][12]14,15 The emerging field of NMR crystallography of organic solids employs experimental solid-state NMR usually in combination with calculation to probe solid-state structures.…”

“…[10][11][12]14,15 The emerging field of NMR crystallography of organic solids employs experimental solid-state NMR usually in combination with calculation to probe solid-state structures. [16][17][18][19][20] In the context of organic molecules, a particular focus is upon the interactions that govern the adopted intermolecular packing, notably hydrogen bonding and aromatic - effects.…”

Pharmaceutical Cocrystals: An Overview

“…Thus, SSNMR is an important tool for the identification of cocrystal or salt. SSNMR can also be used to evaluate the cocrystal structure by estimating hydrogen bonding and local conformation changes by couplings [110,111] .…”

Investigation of Carbohydrates and Their Derivatives as Crystallization Modifiers

“…Particularly, its ability to prove or disprove molecular association and possibility to observe structural features (such as hydrogen bonding) are great advantages of this method. These advantages can be utilized in the analysis of pharmaceutical co-crystals, which are often initially produced using solvent drop grinding techniques that do not lend themselves to single-crystal growth for X-ray diffraction studies (Vogt et al, 2009). …”