Mihaela Pop

Tiotropium Fumarate: An Interesting Pharmaceutical Co-Crystal

A new salt-co-crystal of tiotropium fumarate with fumaric acid has been discovered, and found to be the most stable solid form of tiotropium fumarate. This type of structure consists of matched cations and anions (a salt) together with a nonionized free acid moiety as the co-former (co-crystal), and is unique amongst the large number of tiotropium salts that have been prepared and characterized. The stoichiometry cation/anion/co-former of 2:1:1 corresponds to a simple polymorph of the 1:1 salt, and its identity as a co-crystal has been established by single-crystal X-ray diffraction with some corroborating evidence from the Raman and infrared spectra. A detailed investigation of the bonding and geometry of the three crystalline forms of the fumarate indicates that the hydrogen bonding motifs are very similar, and that conformational differences arising from the packing of the two thiophene rings into the crystal structure is probably important in determining their relative stabilities. A comparison with the structures of other tiotropium salts indicates that there is a correlation of the dihedral angle between the two tiotropium thiophene rings with the stability of the crystal forms.

Crystal structure of the inclusion complex of β-cyclodextrin with mefenamic acid from high-resolution synchrotron powder-diffraction data in combination with molecular-mechanics calculations

The crystal structure of the inclusion complex of beta-cyclo-dextrin with mefenamic acid has been determined from a combination of high-resolution synchrotron powder-diffraction data and molecular-mechanics calculations. A grid search indicates two possible solutions, which are corroborated by molecular-mechanics calculations, while Rietveld-refinement results suggest the crystal structure that is more likely to be formed in the solid state. Mefenamic acid is partially included in beta-cyclodextrin with either the xylyl or the benzoic-acid moiety being inside its cavity. In both solutions mefenamic acid and beta-cyclodextrin form a monomeric complex in a herringbone packing scheme.

Structure of the inclusion complex of β-cyclodextrin with lipoic acid from laboratory powder diffraction data.

The crystal structure of the inclusion complex of β-cyclodextrin with lipoic acid was determined from laboratory powder diffraction data. Thermogravimetric data was used to estimate the number of water molecules in the crystal structure. Lipoic acid is included in β-cyclodextrin through its primary face with the five-membered ring reaching the center plane of the cyclodextrin cavity and its fatty acid chain adopting a bent conformation. Lipoic acid and β-cyclodextrin form a channel-like packing which is stabilized by guest-host hydrogen bonding and close contacts, host-host intermolecular interactions and hydrogen bonding involving the water molecules.

Crystal Structure and Desolvation Behaviour of the Tadalafil Monosolvates with Acetone and Methyl Ethyl Ketone

Crystal structures of Tadalafil (TDF) monosolvated forms with acetone (ACE) and methyl ethyl ketone (MEK) were determined by single-crystal X-ray diffraction in which same persistent chains of TDF molecules are present as in the reported structures. The solvates crystallize in a higher orthorhombic symmetry than the known forms with monoclinic structures. Weak interactions between TDF and solvent molecules are present in both solvates, leading to slight conformational distortions of TDF molecules. The MEK solvate showed slightly higher stability than the ACE solvate, regardless of their highly similar molecular conformations and crystal packing. Desolvation into anhydrous TDF was achieved by heating, exposure to temperature and relative humidity and by mechanical stress. The high solubility of TDF in ACE and MEK solvents combined with the ease of desolvation of the resulting solvated forms indicates the viability of the solvates use as intermediates in the TDF crystallization process.

Fast electron diffraction tomography on beam sensitive materials at room temperature: pharmaceuticals and zeolites

Collecting electron diffraction data suitable for structure solution on beam sensitive materials is a challenging task. Pharmaceuticals and zeolites belong are extremely beam sensitive materials and in most of the cases they amorphize after few minutes when exposed to an electron beam strong enough for collecting a readable electron diffraction pattern with a conventional CCD. Here we present a method that couples the fast electron diffraction tomography (FEDT) [1] procedure with the Timepix single electron detection device [2]. In FEDT the patterns, in precession mode, are collected sequentially by the detector while the crystal is tilting. Due to the fast read-out and high sensitivity of the Timepix detector the FEDT data collection can be carried out with the crystal tilting at a speed of 2°/s or higher without any loss of reciprocal space volume. Crystals can be searched in STEM avoiding beam damage caused by the continuous TEM illumination. During diffraction data collection at room temperature, the electron dose rate can be reduced to the minimum available by the microscope settings, and weak diffraction reflections can be recorded thanks to the zero noise level of the Timepix, after the inelastic background is cut-out by the in-column energy filter. The high stability of the goniometer allows data collection of 90° of reciprocal space coverage in about 30-45 seconds. We demonstrate the efficiency of the method on the structure solution of the cowlesite zeolite, which degrades too fast under the beam for a standard steady-step data acquisition. As a further test for the efficiency of FEDT+Timepix procedure, the structure solution of a pharmaceutical compound is also presented together with the comparison of the crystal model refined by single crystal x-ray diffraction, in order to show the accuracy of electron data on such a compound. References [1] Gemmi M, La Placa MGI, Galanis AS, Rauch EF, Nicolopoulos S (2015) J. Appl. Cryst. 48, 718-727. [2] Van Genderen E, Clabbers MTB, Das PP, Stewart A, Nederlof I, Barentsen KC, Portillo Q, Pannu NS, Nicolopoulos S, Gruene T, Abrahams JP (2016) Acta Cryst. A72, 236-242.

Crystal Structure and Physicochemical Characterization of Ambazone Monohydrate, Anhydrous, and Acetate Salt Solvate

The crystal structures of the monohydrate and anhydrous forms of ambazone were determined by single-crystal X-ray diffraction (SC-XRD). Ambazone monohydrate is characterized by an infinite three-dimensional network involving the water molecules, whereas anhydrous ambazone forms a two-dimensional network via hydrogen bonds. The reversible transformation between the monohydrate and anhydrous forms of ambazone was evidenced by thermal analysis, temperature-dependent X-ray powder diffraction and accelerated stability at elevated temperature, and relative humidity (RH). Additionally, a novel ambazone acetate salt solvate form was obtained and its nature was elucidated by SC-XRD. Powder dissolution measurements revealed a substantial solubility and dissolution rate improvement of acetate salt solvated form in water and physiological media compared with ambazone forms. Also, the acetate salt solvate displayed good thermal and solution stability but it transformed to the monohydrate on storage at elevated temperature and RH. Our study shows that despite the requirement for controlled storage conditions, the acetate salt solvated form could be an alternative to ambazone when solubility and bioavailability improvement is critical for the clinical efficacy of the drug product.

Crystal structure determination of Efavirenz

Needle-shaped single crystals of the title compound, C14H9ClF3NO2, were obtained from a co-crystallization experiment of Efavirenz with maleic acid in a (1:1) ratio, using methanol as solvent. Crystal structure determination at room temperature revealed a significant anisotropy of the lattice expansion compared to the previously reported low-temperature structure. In both low- and room temperature structures the cyclopropylethynyl fragment in one of the asymmetric unit molecules is disordered. While at low-temperature only one C atom exhibits positional disorder, at room temperature the disorder is present for two C atoms of the cyclopropane ring.

N-Butyl-4-butyl­imino-2-methyl­pentan-2-aminium (E)-quercetinate

The title salt, C14H31N2 +·C15H9O7 −, was obtained in the reaction of quercetin with n-butylamine in a mixture of acetone and hexane. The crystal structure determination shows that the quercetin donates one of its phenol H atoms to the N-butyl-4-butylimino-2-methylpentan-2-amine molecule. The crystal structure of the salt is stabilized by intramolecular (N—H⋯N for the cation and O—H⋯O for the anion) and intermolecular hydrogen bonding (N—H⋯O between cation–anion pairs and O—H⋯O between anions). Quercetin molecules form dimers connected into a two-dimensional network. The dihedral angle between the quercetin ring systems is 19.61 (8)°.