Crystal Structure of Linagliptin Hemihydrate Hemiethanolate (C₂₅H₂₈N₈O₂)₂(H₂O)(C₂H₅OH) from 3D Electron Diffraction Data, Rietveld Refinement, and Density Functional Theory Optimization

Abstract

The crystal structure of linagliptin hemihydrate hemiethanolate was solved by direct methods and refined by least-squares on the basis of 3D electron diffraction data. Linagliptin is one of the largest organic structures solved ab initio by electron diffraction. The good quality of the data allows the recognition of subtle symmetry reductions and of fine differences in the configuration of the two independent molecules that make up the structure. The structure was then further refined using synchrotron X-ray powder diffraction data and optimized using density functional techniques. The linagliptin hemihydrate hemiethanolate structure is very similar to the known linagliptin water/methanol/ethanol Form I, and crystallizes in space group P21212 (#18) with a = 24.85091(13), b = 21.56916(9), c = 9.74376(4) Å, V = 5222.79(3) Å3, and Z = 4. Although the compounds are similar, they are not the same, so the linagliptin hemihydrate hemiethanolate structure is a novel one. The powder pattern from a Le Bail fit to synchrotron data is included in the Powder Diffraction File as entry 00-066-1626.

3D Electron Diffraction Structure Determination of Terrylene, a Promising Candidate for Intermolecular Singlet Fission

“…Due to the small amount of sample and its extremely anisotropic crystal habit, the terrylene structure could not be validated by Rietveld refinement against powder XRD data, as has been proposed in previous works. [ 20 , 25 , 26 ] This is unfortunately a rather common situation for organic samples. [ 22 , 29 , 84 ]…”

“… [9] In recent years, 3D ED has been extensively used for the structure determination of various nanocrystalline materials, ranging from inorganics to macromolecules. [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ] In the world of small‐molecule organic compounds, 3D ED has been successfully employed for unveiling the structure of organic frameworks, [19] semiconductors [20] peptides,[ 21 , 22 ] pharmaceuticals[ 23 , 24 , 25 , 26 ] and natural products,[ 27 , 28 , 29 ] all of which could not be addressed by XRD methods.…”

A Comparison of Structure Determination of Small Organic Molecules by 3D Electron Diffraction at Cryogenic and Room Temperature

“…This was the first time that such a hybrid pixel detector was used for collecting 3D ED data, which has the advantages of high sensitivity, low noise and, short readout time. Later, several articles [11][12][13][14][15][16][17] described the routine of rapid structure determination for small organic molecules using 3D ED. Palatinus et al showed that it was possible to determine hydrogen positions in both organic (paracetamol) and inorganic crystals by employing dynamical refinements [18].…”

Strategies for structure solution of small-molecule organics by 3D-ED using a small beam

“…Still, global optimisation approaches, like simulated annealing [6], are valuable alternatives when data are affected by low resolution, preferential orientation or experimental errors that compromise the overall intensity reliability (e.g. beam damage, merohedric twinning, diffuse scattering).We will thus discuss examples of recently published [7,8] and forthcoming structure characterizations of pharmaceutical compounds, organic charge-transfer co-crystals and polycyclic aromatic hydrocarbons. For each case, specific problematics of the sample will be discussed, together with experimental solutions adopted for achieving structural solution and refinement.…”

“…We will thus discuss examples of recently published [7,8] and forthcoming structure characterizations of pharmaceutical compounds, organic charge-transfer co-crystals and polycyclic aromatic hydrocarbons. For each case, specific problematics of the sample will be discussed, together with experimental solutions adopted for achieving structural solution and refinement.…”