The neutron powder diffractometer POWGEN at the Spallation Neutron Source has recently (2017–2018) undergone an upgrade which resulted in an increased detector complement along with a full overhaul of the structural design of the instrument. The current instrument has a solid angular coverage of 1.2 steradians and maintains the original third-generation concept, providing a single-histogram data set over a wide d-spacing range and high resolution to access large unit cells, detailed structural refinements and in situ/operando measurements.

https://journals.iucr.org/j/issues/2019/05/00/in5025/in5025.pdf

POWGEN: rebuild of a third-generation powder diffractometer at the Spallation Neutron Source

The crystal structures of (NH4)H2C6H5O7 and (NH4)3C6H5O7 have been determined using a combination of powder and single crystal techniques. The structure of (NH4)2HC6H5O7 has been determined previously by single crystal diffraction. All three structures were optimized using density functional techniques. The crystal structures are dominated by N-H⋅⋅⋅O hydrogen bonds, though O-H⋅⋅⋅O hydrogen bonds are also important. In (NH4)H2C6H5O7 very strong centrosymmetric charge-assisted O-H-O hydrogen bonds link one end of the citrate into chains along the b-axis. A more-normal O-H⋅⋅⋅O hydrogen bond links the other end of the citrate to the central ionized carboxyl group. In (NH4)2HC6H5O7, the very strong centrosymmetric O-H-O hydrogen bonds link the citrates into zig-zag chains along the b-axis. The citrates occupy layers parallel to the bc plane, and the ammonium ions link the layers through N-H⋅⋅⋅O hydrogen bonds. In (NH4)3C6H5O7, the hydroxyl group forms a hydrogen bond to a terminal carboxylate, and there is an extensive array of N-H⋅⋅⋅O hydrogen bonds. The energies of the density functional theory-optimized structures lead to a correlation between the energy of an N-H⋅⋅⋅O hydrogen bond and the Mulliken overlap population: E(N-H⋅⋅⋅O) (kcal/mole) = 23.1(overlap)½. Powder patterns of (NH4)H2C6H5O7 and (NH4)3C6H5O7 have been submitted to International Centre for Diffraction Data for inclusion in the powder diffraction file.

Crystal structures of ammonium citrates

Fluorinated drugs occupy a large and growing share of the pharmaceutical market. Here, we explore high-frequency, 60 to 111 kHz, 19F magic-angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy for the structural characterization of fluorinated active pharmaceutical ingredients in commercial formulations of seven blockbuster drugs: Celebrex, Cipro, Crestor, Levaquin, Lipitor, Prozac, and Zyvox. 19F signals can be observed in a single scan, and spectra with high signal-to-noise ratios can be acquired in minutes. 19F spectral parameters, such as chemical shifts and line widths, are sensitive to both the nature of the fluorine moiety and the formulation. We anticipate that the fast 19F MAS NMR-based approach presented here will be valuable for the rapid analysis of fluorine-containing drugs in a wide variety of formulations.

Fast 19F Magic-Angle Spinning Nuclear Magnetic Resonance for the Structural Characterization of Active Pharmaceutical Ingredients in Blockbuster Drugs.

The aim of this study was to characterize a 1:1 molar ratio of a pharmacologically relevant co-amorphous atorvastatin-irbesartan (ATR-IRB) system obtained by quench cooling of the crystalline ATR/IRB physical mixture for potential use in the fixed-dose combination therapy. The system was characterized by employing standard differential scanning calorimetry (DSC), Fourier transform-infrared spectroscopy (FT-IR), and intrinsic dissolution rate studies. Quantum mechanical calculations were performed to obtain information regarding intermolecular interactions in the studied co-amorphous ATR-IRB system. The co-amorphous formulation showed a significant improvement in the intrinsic dissolution rate (IDR) of IRB over pure crystalline as well as its amorphous counterpart. An unusual behavior was observed for ATR, as the IDR of ATR in the co-amorphous formulation was slightly lower than that of amorphous ATR alone. Short-term physical aging studies of up to 8 h proved that the ATR-IRB co-amorphous system remained in the amorphous form. Furthermore, no physical aging occurred in the co-amorphous system. FT-IR, density functional theory calculations, and analysis of Tg value of co-amorphous system using the Couchman–Karasz equation revealed the presence of molecular interactions between APIs, which may contribute to the increased physical stability.

https://www.mdpi.com/1999-4923/13/1/118/pdf

Physicochemical Characterization of a Co-Amorphous Atorvastatin-Irbesartan System with a Potential Application in Fixed-Dose Combination Therapy

Structure determination, thermal stability and dissolution rate of δ-indomethacin.

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 lar...

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

New compounds of the type LiMHC6H5O7 (M = Li, Na, K, Rb) have been prepared from the metal carbonates and citric acid in solution. The crystal structures have been solved and refined using laboratory powder X-ray diffraction data, and optimized using density functional techniques. The compounds crystallize in the triclinic space group P\overline 1 and are nearly isostructural. The structures are lamellar, with the layers in the ab plane. The boundaries of the layers consist of hydro­phobic methyl­ene groups and very strong inter­molecular O—H⋯O hydrogen bonds. The O⋯O distances range from 2.666 A for M = Li to 2.465 A for M = Rb. The Li—O bonds exhibit significant covalent character, while the heavier M—O bonds are ionic. The Li atoms are four-, five-, or six-coordinate, while the coordination numbers of the larger cations are higher, i.e. eight for Na and nine for K and Rb. The citrate anion occurs in the trans,trans conformation, one of the two low-energy conformations of an isolated citrate anion. The crystal structure of LiRbHC6H5O7·H2O was also solved and refined. It consists of the same layers as in the anhydrous M = Rb compound, with inter­layer water mol­ecules and a different hydrogen-bonding pattern.

Dilithium (citrate) crystals and their relatives

The crystal structure of sodium rubidium hydrogen citrate, NaRbHC6H5O7 or [NaRb(C6H6O7)]n, has been solved and refined using laboratory powder X-ray diffraction data, and optimized using density functional techniques. This compound is isostructural to NaKHC6H5O7. The Na atom is six-coordinate, with a bond-valence sum of 1.16. The Rb atom is eight-coordinate, with a bond-valence sum of 1.17. The distorted [NaO6] octa­hedra share edges to form chains along the a-axis direction. The irregular [RbO8] coordination polyhedra share edges with the [NaO6] octa­hedra on either side of the chain, and share corners with other Rb atoms, resulting in triple chains along the a-axis direction. The most prominent feature of the structure is the chain along [111] of very short, very strong hydrogen bonds; the O⋯O distances are 2.426 and 2.398 A. The Mulliken overlap populations in these hydrogen bonds are 0.140 and 0.143 electrons, which correspond to hydrogen-bond energies of about 20.3 kcal mol−1. The crystal structure of sodium caesium hydrogen citrate, NaCsHC6H5O7 or [NaCs(C6H6O7)]n, has also been solved and refined using laboratory powder X-ray diffraction data, and optimized using density functional techniques. The Na atom is six-coordinate, with a bond-valence sum of 1.15. The Cs atom is eight-coordinate, with a bond-valence sum of 0.97. The distorted trigonal–prismatic [NaO6] coordination polyhedra share edges to form zigzag chains along the b-axis direction. The irregular [CsO8] coordination polyhedra share edges with the [NaO6] polyhedra to form layers parallel to the (101) plane, unlike the isolated chains in NaKHC6H5O7 and NaRbHC6H5O7. A prominent feature of the structure is the chain along [100] of very short, very strong O—H⋯O hydrogen bonds; the refined O⋯O distances are 2.398 and 2.159 A, and the optimized distances are 2.398 and 2.347 A. The Mulliken overlap populations in these hydrogen bonds are 0.143 and 0.133 electrons, which correspond to hydrogen-bond energies about 20.3 kcal mol−1.

https://journals.iucr.org/e/issues/2019/02/00/vn2138/vn2138.pdf

Sodium rubidium hydrogen citrate, NaRbHC6H5O7, and sodium caesium hydrogen citrate, NaCsHC6H5O7: crystal structures and DFT comparisons.

The crystal structure of eltrombopag olamine Form I has been solved and refined using synchrotron X-ray powder diffraction data and optimized using density functional techniques. Eltrombopag olamine crystallizes in the space group P21/n (#14) with a = 17.65884(13), b = 7.55980(2), c = 22.02908(16) A, β = 105.8749(4)°, V = 2828.665(11) A3, and Z = 4. The crystal structure is dominated by columns of hydrogen-bonded cations and anions along the short b-axis. van der Waals interactions bind the columns together. Two H atoms of each ammonium group in the ethanolammonium cations participate in strong hydrogen bonds, and the third H forms weaker bifurcated H-bonds. The powder pattern has been submitted to ICDD® for inclusion in the Powder Diffraction File™ (PDF®).

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/13725B686DBCEEBE501DD7A063E060D6/S0885715621000099a.pdf/div-class-title-crystal-structure-of-eltrombopag-olamine-form-i-c-span-class-sub-2-span-h-span-class-sub-8-span-no-span-class-sub-2-span-c-span-class-sub-25-span-h-span-class-sub-20-span-n-span-class-sub-4-span-o-span-class-sub-4-span-div.pdf

James A. Kaduk

Papers

Crystal structures of ammonium citrates

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

Dilithium (citrate) crystals and their relatives

Sodium rubidium hydrogen citrate, NaRbHC6H5O7, and sodium caesium hydrogen citrate, NaCsHC6H5O7: crystal structures and DFT comparisons.

Crystal structure of eltrombopag olamine Form I, (C2H8NO)2 (C25H20N4O4)