Volker Kahlenberg

Conformational polymorphism in aripiprazole: Preparation, stability and structure of five modifications

Five phase-pure modifications of the antipsychotic drug aripiprazole were prepared and characterized by thermal analysis, vibrational spectroscopy and X-ray diffractometry. All modifications can be produced from solvents, form I additionally by heating of form X degrees to approximately 120 degrees C (solid-solid transformation) and form III by crystallization from the melt. Thermodynamic relationships between the polymorphs were evaluated on the basis of thermochemical data and visualized in a semi-schematic energy/temperature diagram. At least six of the ten polymorphic pairs are enantiotropically and two monotropically related. Form X degrees is the thermodynamically stable modification at 20 degrees C, form II is stable in a window from about 62-77 degrees C, and form I above 80 degrees C (high-temperature form). Forms III and IV are triclinic (

One-pot covalent and supramolecular synthesis of pharmaceutical co-crystals using the API isoniazid: a potential supramolecular reagent

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Crystal chemistry of GdScO3, DyScO3, SmScO3 and NdScO3

), I and X degrees are monoclinic (P2(1)) and form II orthorhombic (Pna2(1)). Each polymorph exhibits a distinct molecular conformation, and there are two fundamental N-H

Solid-state forms of β-resorcylic acid how exhaustive should a polymorph screen be?

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Packing polymorphism of a conformationally flexible molecule (aprepitant)

O hydrogen bond synthons (catemers and dimers). Hirshfeld surface analysis was employed to display differences in intermolecular short contacts. A high kinetic stability was observed for three metastable polymorphs which can be categorized as suitable candidates for the development of solid dosage forms.

Rietveld analysis of dicalcium aluminate (Ca2Al2O5)—A new high pressure phase with the Brownmillerite-type structure

The synthon approach has been applied to synthesizing pharmaceutical co-crystals using the anti-tuberculosis drug isonicotinic acid hydrazide (ISONIAZID). Isoniazid has the potential to be a supramolecular reagent and so far has been put to very limited use in making co-crystals. In this report, we co-crystallize isoniazid with the dicarboxylic acids malonic (1), succinic (2), glutaric (3), adipic (4) and pimelic acid (5), and the monocarboxylic acids 4-hydroxybenzoic acid (6) and 2,4-dihydroxybenzoic acid (7). By surveying the literature through the Cambridge Structural Database, we identified the possible homosynthons and heterosynthons that are likely to form in the co-crystallization of isonizaid with carboxylic acids. The dominant interaction is the COOH⋯N hydrogen bond, which is used in all seven co-crystals. In addition, we present an example in which both a covalent and supramolecular synthesis occurs without affecting the vital supramolecular co-crystal forming synthon, the carboxylic acid⋯pyridine pair functionality, by reacting isoniazid with 2-butanone and acetone while co-crystallizing it with 3-hydroxybenzoic acid (8 and 9) in a one-pot synthesis.

Incommensurately modulated ordering of tetra­hedral chains in Ca2Fe2O5 at elevated temperatures

The crystal chemistry of GdScO3 and, for the first time, of DyScO3, SmScO3 and NdScO3 has been investigated using single crystals. The structure of the Czochralski grown crystals was refined from single crystal X-ray diffraction data, their chemical compositions were analysed by inductively coupled plasma optical emission spectrometry (ICP OES). Orthorhombic distorted perovskite structure types with the space group Pnma could be confirmed in all cases. The B-site of the lanthanoid scandates shows with 2.090 to 2.116 Å typical bond lengths for octahedrally coordinated scandium. The distortion of the B-site is rather small. The A-site is occupied by the lanthanoid (Ln) and the Ln—O bond distances vary from 2.233 to 3.722 Å. This indicates its high distortion and makes an assignment of the coordination number difficult. However, an 8-fold coordination for the A-site has to be assumed. The Ln-scandates show a continuous structural evolution with the size of the lanthanoid. A discontinuity within the intermediate members of the Ln-scandates — which had previously been described — was not observed. The ICP OES investigation of these samples results in non-stoichiometric chemical compositions: the chemical analyses show always a depletion in the lanthanoid. Site occupancy refinements based on single crystal diffraction data support the idea of the Ln-depletion on the A-site (inducing O-defects on the O2-position). Several substitution mechanisms are discussed, but the authors favour that vacancies on the A-site coupled with oxygen vacancies cause the Ln-deficiencies. The crystallochemical formula of the investigated Ln-scandates may be written as: (∀0.056Dy0.944)ScO2.916,(∀0.048Gd0.952)ScO2.928, (∀0.045Sm0.955)ScO2.933 and (∀0.033Nd0.967)ScO2.951.

Absorbing a Little Water: The Structural, Thermodynamic,and Kinetic Relationship between Pyrogallol and Its Tetarto-Hydrate

A combined experimental and computational study was undertaken to establish the solid-state forms of β-resorcylic acid (2,4-dihydroxybenzoic acid). The experimental search resulted in nine crystalline forms: two concomitantly crystallizing polymorphs, five novel solvates (with acetic acid, dimethyl sulfoxide, 1,4-dioxane, and two with N,N-dimethyl formamide), in addition to the known hemihydrate and a new monohydrate. Form II°, the thermodynamically stable polymorph at room temperature, was found to be the dominant crystallization product. A new, enantiotropically related polymorph (form I) was obtained by desolvation of certain solvates, sublimation experiments, and via a thermally induced solid−solid transformation of form II° above 150 °C. To establish their structural features, interconversions, and relative stability, all solid-state forms were characterized with thermal, spectroscopic, X-ray crystallographic methods, and moisture-sorption analysis. The hemihydrate is very stable, while the five solvates and the monohydrate are rather unstable phases that occur as crystallization intermediates. Complementary computational work confirmed that the two experimentally observed β-resorcylic acid forms I and II° are the most probable polymorphs and supported the experimental evidence for form I being disordered in the p-OH proton position. These consistent outcomes suggest that the most practically important features of β-resorcylic acid crystallization under ambient conditions have been established; however, it appears impractical to guarantee that no additional metastable solid-state form could be found.

Insights into hydrate formation and stability of morphinanes from a combination of experimental and computational approaches.

This work highlights the structural and thermochemical differences of two modifications of the NK1receptor antagonist aprepitant. Form I° is the stable polymorph and crystallises in the orthorhombic space groupP212121 whereas the metastable form II is monoclinic (space groupP21). The monotropically related polymorphs show only minor differences in melting point and heat of fusion (Tfus,I = 253.6, ΔfusHI = 53.7 kJ mol−1, Tfus,II = 253.0 °C, ΔfusHII = 52.4 kJ mol−1) and often crystallise concomitantly. The forms exhibit a very close structural relationship based on a common 2D packing fragment, which is in fact a stack of 1D N–H⋯O hydrogen bonded ribbon chains. Forms I° and II may therefore be interpreted as two distinct stacking modes of this common 2D unit. The alternative modes are associated with slight differences in weaker intermolecular interactions. Somewhat surprisingly, the aprepitant molecule adopts almost the same conformation in the two crystal structures in spite of its potential conformational flexibility. Hirshfeld surface analysis was successfully deployed to visualise and elaborate the small differences in the molecular environments of the two polymorphs. The study emphasises the benefit of single-crystal structure data for the judgement of the phase purity and of polymorphs exhibiting only weak energetical and structural differences.

Crystal structure of hexagonal trinepheline; a new synthetic NaAlSiO 4 modification

Abstract Dicalcium aluminate (Ca2Al2O5) was prepared in a piston cylinder apparatus at 1250 °C and 2.5 GPa. The compound is orthorhombic with space group symmetry /2mb, a = 5.2281(1) Å, b = 14.4686(2) Å, c = 5.4004(1) Å (Z = 4, Dcalc = 3.481 g/cm3), and belongs to the brownmillerite structure family. Main building units are (1) layers of perovskite type corner connected AlO6-octahedra perpendicular to [010], and (2) zweier single chains of AlO4-tetrahedra running parallel [100]. The alternate stacking of the layers and sheets of single chains results in a three dimensional network in which the calcium ions are incorporated for charge compensation. The present structure is the first example for an alkaline earth aluminate with zweier single chains of tetrahedra.