Jürgen Brüning

The Thermodynamically Stable Form of Solid Barbituric Acid: The Enol Tautomer

Barbituric acid, which has been known since 1863, is drawn in textbooks always as the keto tautomeric form 1 (Scheme 1). Indeed, this is the most stable form in the gas phase and in solution. Also in the solid state, the keto tautomer is observed in the metastable phase I, the commercial phase II, and a high-temperature phase III, as well as in its dihydrates. In contrast, we now observe that the recently discovered tautomeric polymorph IV consists of molecules in the enol form 2, and that this polymorph is actually the thermodynamically stable phase at ambient conditions. The preference for the enol form in the solid state is explained by the formation of an additional strong hydrogen bond in the crystal, leading to a more favorable lattice energy. Polymorph IV is obtained from phase II by grinding or milling. Solid-state NMR (SSNMR), IR, and Raman experiments revealed this to be a tautomeric polymorph, which does not consist of the keto tautomer 1, but of one of the enol forms. The spectroscopic data suggested the trienol tautomer, but other enol tautomers could not be ruled out. All attempts to obtain single crystals of phase IV by recrystallization failed, and dehydration of the dihydrate yielded only phase II. The grinding or milling processes resulted in powders of poor crystallinity. However, it was possible to index the laboratory X-ray powder data and to solve the crystal structure by simulated annealing, while refinement was carried out by the Rietveld method from synchrotron data (Figure 1). The bond lengths in the OCN framework revealed phase IV to consist of molecules in the enol form 2. Scheme 1. Barbituric acid in the keto (1) and enol (2) tautomeric forms.

X-ray powder diffraction, solid-state NMR and dispersion-corrected DFT calculations to investigate the solid-state structure of 2-ammonio-5-chloro-4-methylbenzenesulfonate

Abstract The title compound, also called CLT acid, is an industrial intermediate in the synthesis of laked red azo pigments for newspaper printing. Solid-state NMR and IR experiments revealed the compound to exist as the zwitterionic tautomer in the solid state. The crystal structure was solved from X-ray powder diffraction data by means of real-space methods using the program DASH 3.1. Subsequently the structure was refined by the Rietveld method with TOPAS 4.1. The zwitterionic tautomer gave better confidence values than the non-zwitterionic tautomer. Finally the structure was confirmed by dispersion-corrected density-functional calculations. The compound crystallises in the monoclinic space group Ia, Z = 4 with a = 5.49809(7) Å, b = 32.8051(5) Å, c = 4.92423(7) Å, β = 93.5011(7)° and V = 886.50(2) Å3. The molecules form a herringbone pattern with a double layer structure consisting of alternating polar and non-polar layers. Within the polar layers hydrogen bonds and ionic interactions are dominant, whereas the fragments in the non-polar layers are connected by van der Waals interactions.

Structure determination of seven phases and solvates of Pigment Yellow 183 and Pigment Yellow 191 from X-ray powder and single-crystal data.

The crystal structures of two industrially produced laked yellow pigments, Pigment Yellow 183 [P.Y. 183, Ca(C16H10Cl2N4O7S2), alpha phase] and Pigment Yellow 191 [P.Y. 191, Ca(C17H13ClN4O7S2), alpha and beta phases], were determined from laboratory X-ray powder diffraction data. The coordinates of the molecular fragments of the crystal structures were found by means of real-space methods (simulated annealing) with the program DASH. The coordinates of the calcium ions and the water molecules were determined by combining real-space methods (DASH and MRIA) and repeated Rietveld refinements (TOPAS) of the partially finished crystal structures. TOPAS was also used for the final Rietveld refinements. The crystal structure of beta-P.Y. 183 was determined from single-crystal data. The alpha phases of the two pigments are isostructural, whereas the beta phases are not. All four phases exhibit a double-layer structure, built from nonpolar layers containing the C/N backbone and polar layers containing the calcium ions, sulfonate groups and water molecules. Furthermore, the crystal structures of an N,N-dimethylformamide solvate of P.Y. 183, and of P.Y. 191 solvates with N,N-dimethylformamide and N,N-dimethylacetamide were determined by single-crystal X-ray analysis.

Electron diffraction, X-ray powder diffraction and pair-distribution-function analyses to determine the crystal structures of Pigment Yellow 213, C23H21N5O9

The crystal structure of the nanocrystalline alpha phase of Pigment Yellow 213 (P.Y. 213) was solved by a combination of single-crystal electron diffraction and X-ray powder diffraction, despite the poor crystallinity of the material. The molecules form an efficient dense packing, which explains the observed insolubility and weather fastness of the pigment. The pair-distribution function (PDF) of the alpha phase is consistent with the determined crystal structure. The beta phase of P.Y. 213 shows even lower crystal quality, so extracting any structural information directly from the diffraction data is not possible. PDF analysis indicates the beta phase to have a columnar structure with a similar local structure as the alpha phase and a domain size in column direction of approximately 4 nm.

The use of dispersion-corrected DFT calculations to prevent an incorrect structure determination from powder data: the case of acetolone, C11H11N3O3

Abstract The crystal structure of acetolone (5-(acetoacetylamino)benzimidazolone, C11H11N3O3), was determined from X-ray powder data. Despite strong preferred orientation effects, the structure could be solved with real-space methods and refined by the Rietveld method using restraints. The resulting structure gave a good Rietveld fit with reasonable confidence values; the structure looked chemically sensible and passed all tests including a CSD check and the checkCIF procedure. But dispersion-corrected density functional theory (DFT) calculations revealed that this structure was actually wrong, and further work showed that the terminal acetyl group had to be rotated by 180°. The correct crystal structure led to a better Rietveld refinement with improved R-values. This structure was confirmed by dispersion-corrected DFT calculations. The compound crystallises in P-1 with two molecules per unit cell. The molecules are connected by a 2-dimensional hydrogen bond network.

The determination of crystal structures of active pharmaceutical ingredients from X-ray powder diffraction data: a brief, practical introduction, with fexofenadine hydrochloride as example

This study describes the general method for the determination of the crystal structures of active pharmaceutical ingredients (API) from powder diffraction data and demonstrates its use to determine the hitherto unknown crystal structure of fexofenadine hydrochloride, a third‐generation antihistamine drug.

Ezetimibe anhydrate, determined from laboratory powder diffraction data.

Ezetimibe {systematic name: (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one}, C(24)H(21)F(2)NO(3), is used to lower cholesterol levels by inhibiting cholesterol resorption in the human intestine. The crystal structure of ezetimibe anhydrate was solved from laboratory powder diffraction data by means of real-space methods using the program DASH [David et al. (2006). J. Appl. Cryst. 39, 910-915]. Subsequent Rietveld refinement with TOPAS Academic [Coelho (2007). TOPAS Academic User Manual. Version 4.1. Coelho Software, Brisbane, Australia] led to a final R(wp) value of 8.19% at 1.75 A resolution. The compound crystallizes in the space group P2(1)2(1)2(1) with one molecule in the asymmetric unit. The molecules are closely packed and two intermolecular hydrogen bonds form an extended hydrogen-bond architecture.

Characterization of a New Solvate of Risedronate

Three new forms of the osteoporosis drug sodium risedronate, sodium [1-hydroxy-2-(3-pyridinyl)ethylidene]bisphosphonate, were identified and designated as the J, K, and M phases. Form J is an acetic acid disolvate with the chemical composition Na(+) [C(7) H(10) NO(7) P(2)](-) · 2CH(3) COOH, as determined by single-crystal structure analysis. This novel solvate is easily formed by the recrystallization of sodium risedronate from acetic acid. Dissolution of the new disolvate was characterized in distilled water, a compendial buffer, simulated gastric fluid sine pepsin (pH 1.2), and a biorelevant buffer system FaSSIF-V2 (pH 6.8). It was demonstrated that solubility of the disolvate in physiological buffers differed significantly from that of the original molecule, with delayed dissolution under simulated esophageal and gastric conditions, but rapid and complete dissolution under simulated intestinal conditions. These studies suggest that through the generation of novel solvates, the biopharmaceutical properties of poorly soluble drug candidates can be improved.

Rasagiline ethanedisulfonate: an inhibitor for monoamine oxygenase B (MAOB)

Rasagiline is a selective and potent drug used for the treatment of Parkinsons disease. The first crystal structure of a salt of rasagiline, the title compound, bis[(1R)-N-prop-2-ynyl-2,3-dihydro-1H-inden-1-aminium] ethanedisulfonate, 2C(12)H(14)N(+).C(2)H(4)O(6)S(2)(-), was determined from crystals grown by gas diffusion. The compound has monoclinic (C2) symmetry. The ethane group of the ethanedisulfonate anion is disordered over three positions. The C(2)-symmetric ethanedisulfonate anions are connected by four N-H...O hydrogen bonds to four rasagiline cations. This leads to large 18-membered rings which are arranged in ladders in the [010] direction. The extended hydrogen-bonding architecture may explain the stability of the structure. Rasagiline ethanedisulfonate is nonhygroscopic. During a polymorph screen, no hydrates, solvates or polymorphs were found.

2-Aminoterephthalic acid dimethyl ester.

Single crystals of the title compound, C10H11NO4, an intermediate in the industrial synthesis of yellow azo pigments, were obtained from the industrial production. The molecules crystallize as centrosymmetic dimers connected by two symmetry-related N—H⋯O=C hydrogen bonds. Each molecule also contains an intramolecular N—H⋯O=C hydrogen bond. The dimers form stacks along the a-axis direction. Neighbouring stacks are arranged into a herringbone structure.