An introduction to the special issue on pharmaceuticals, drug discovery and natural products

An overview of current topics of interest in the field of solid-state pharmaceuticals and an introduction to papers featured in this special issue.

Structural assignment of a bis-cyclo­pentenyl-β-cyano­hydrin formed via alkene metathesis from either a triene or a tetra­ene precursor

Density functional theory (DFT) NMR prediction, ¹H–¹H Total Correlated Spectroscopy (TOCSY) NMR and single-crystal X-ray crystallography were used to confirm the formation of a bis-cyclo­pentenyl-β-cyano­hydrin in preference to a 2,3,6,7-de­hydro­deca­lin-β-cyano­hydrin as the kinetic product upon subjecting tri- and tetra­ene substrates to Ru-catalyzed alkene metathesis.

Absolute configuration of naturally occurring glabridin

Glabridin is a species-specific biomarker from the roots Glycyrrhiza glabra L. (European licorice, Fabaceae). Stereochemical analysis, including circular dichroism, NMR data and an X-ray diffraction data set with Bijvoet differences, confirms that glabridin, purified from its natural source, is found only in a C3 R configuration.

A new polymorph of N-(6-methyl­pyridin-2-yl)mesityl­ene­sulfon­amide

A new polymorph of the pharmaceutically active sulfa­pyridine derivative N-(6-methyl­pyridin-2-yl)mesityl­ene­sulfon­amide was obtained as a phase-pure product from methanol. The mol­ecules adopt the conformation which is predicted for an individual mol­ecule by force field calculations.

Bis[4-amino-N-(pyrimidin-2-yl)benzene­sulfonamido]­diamminecopper(II): aqua or ammine ligands?

High-resolution diffraction data support our interpretation that the title compound is coordinated by two ammine rather than by an ammine and an aqua ligand.

Preparation and structural analysis of (±)-threo-ritalinic acid

The preparation, single-crystal X-ray structure and solution-state NMR analysis of (±)-threo-ritalinic acid, obtained from the hydrolysis of the methyl ester (±)-threo-methyl phenidate, are reported.

Structures of cefradine dihydrate and cefaclor dihydrate from DFT-D calculations

The isostructural crystal structures of cefradine dihydrate and cefaclor dihydrate, based on experimental data where available and supplemented with dispersion-corrected density functional theory calculations, are presented. The crystal structures are typical examples of isolated-site hydrates.

Enantio­tropically related polymorphs of gaboxadol hydro­chloride

Gaboxadol hydrochloride (also known as THIP hydrochloride) undergoes a reversible single-crystal-to-single-crystal transformation at 221 K. Crystal structures have been determined at 298 and 220 K.

Crystal structure and packing energy calculations of (+)-6-amino­penicillanic acid

(+)-6-Amino­penicillanic acid, a precursor of a variety of semi-synthetic penicillins, represents an ordered zwitterion and the crystals are nonmerohedrally twinned. The complementary analysis of the crystal packing by the PIXEL method brings to light the nature and ranking of the energetically most stabilizing inter­molecular inter­action energies.

Structural and docking studies of potent e­thio­namide boosters

This report illustrates the crystal structures of three new inhibitors targeting the mycobacterial regulator EthR which has previously been identified as a novel target for tuberculosis drug boosters. In addition, we describe how the results of our structure determination were used to develop a docking protocol using GOLD for future in silico screening.

The principles underlying the use of powder diffraction data in solving pharmaceutical crystal structures

Solving pharmaceutical crystal structures from powder diffraction data is discussed in terms of both the various methodologies that have been applied and the complexity of the structures that have been solved.

Methane­sulfonic acid salt forms of carbamazepine and 10,11-di­hydro­carbamazepine

Methane­sulfonic acid salt forms of carbamazepine and 10,11-di­hydro­carbamazepine have been prepared and characterized by a number of analytical techniques, including single-crystal X-ray diffraction at 100 K. The structural data for these complexes were analysed in relation to data derived from other carbamazepine complexes and a redetermination of the apparently anomalous tri­fluoro­acetic acid solvate structure was undertaken.

A 1:2 cocrystal of genistein with isonicotinamide: crystal structure and Hirshfeld surface analysis

The mol­ecules in the title cocrystal are present in their neutral forms, and assemble a mol­ecular layer by means of hydrogen bonding. Differences in the environments of the isonicotinamide molecules were assessed by Hirshfeld surface analysis.

A complementary experimental and computational study of loxapine succinate and its monohydrate

The structure determination of loxapine succinate and its monohydrate is presented. Fixed cell geometry optimization using density functional theory in CASTEP was used as a complementary tool to locate the H-atom positions in the crystal structure determined from X-ray powder diffraction data.

Utilizing proton transfer to produce mol­ecular salts in bromanilic acid substituted-pyridine mol­ecular complexes – predictable synthons?

Proton transfer systematically producing mol­ecular salts is used in a study of nine mol­ecular complexes of bromanilic acid with methyl­pyridines, which show predictable synthons related to the stoichiometry and a common N—H⋯O charge-assisted hydrogen bond.

MYb(BH₄)₄ (M = K, Na) from laboratory X-ray powder data

The title compounds were prepared via a mechano­chemical reaction in the solid state. They crystallize in the NaSc(BH₄)₄ structure type composed of isolated [Yb(BH₄)₄]⁻ anions, with Yb coordinated tetra­hedrally by BH₄ groups, surrounded by M⁺ cations (M = Na, K) which form distorted trigonal prisms.

Crystal structures of hydrates of simple inorganic salts. I. Water-rich magnesium halide hydrates MgCl₂·8H₂O, MgCl₂·12H₂O, MgBr₂·6H₂O, MgBr₂·9H₂O, MgI₂·8H₂O and MgI₂·9H₂O

Crystals of MgCl₂·8H₂O, MgCl₂·12H₂O, MgBr₂·6H₂O, MgBr₂·9H₂O, MgI₂·8H₂O and MgI₂·9H₂O were grown from their aqueous solutions at temperatures below 298 K according to the solid–liquid phase diagrams. All structures are built up from Mg(H₂O)₆ octa­hedra. Dimensions and angles in the hexa­aqua cation complexes are very similar and variation is not systematic.

The double molybdate Na₉Sc(MoO₄)₆ refined from powder XRD data

Rietveld refinement of Na₉Sc(MoO₄)₆ shows that its structure is made up of clusters formed from an ScO₆ octa­hedron and three Na1O₆ octa­hedra sharing total edges. The clusters are connected by sharing vertices with bridging MoO₄ tetra­hedra, forming a three-dimensional framework.

The organic–inorganic hybrid material 1-cyclo­hexyl­piperazine-1,4-diium tetra­chlorido­zincate

In the title organic–inorganic hybrid material, the tetra­chlorido­zincate anions and 1-cyclo­hexyl­piperazine-1,4-diium dications are inter­connected via N—H⋯Cl and C—H⋯Cl hydrogen bonds to form layers parallel to the (001) plane. The cyclo­hexyl groups are located between these layers to form an infinite three-dimensional network.

A one-dimensional coordination polymer created via in situ ligand synthesis involving C—N bond formation

A novel cadmium complex consists of one-dimensional ladders constructed from [Cd₂(COO)₂] dimeric subunits. A combination of hydrogen bonding and π–π stacking inter­actions extend the one-dimensional ladders into a three-dimensional supra­molecular architecture.

A two-dimensional network con­taining an –Mn—O—C—O—Mn– chain: poly[di­aqua[1,2-bis­(pyridin-4-yl)ethylene][μ₃-3-carb­oxy-5-(carboxylato­meth­oxy)benzoato]manganese(II)]

The title compound is a two-dimensional network containing an –Mn—O—C—O—Mn– chain. Each layer presents a herringbone pattern and interacts with neighbouring layers through intermolecular hydrogen bonds.

The purine–carboxylate-containing coordination polymer poly[[μ₄-1-(2-carboxyl­ato­ethyl)-6-oxo-6,9-di­hydro-1H-purin-9-ido]zinc(II)]

A three-dimensional metallohelicate is constructed from one-dimensional metal–organic helices of purine-containing 3-(6-oxo-6,9-di­hydro-1H-purin-1-yl)propionate ligands and zinc(II) ions.

3,4-Dihy­droxy-1,6-bis­(4-meth­oxy­phen­yl)hexa-2,4-diene-1,6-dione, its 4-methyl­phenyl analogue, and a potassium salt of 2-hy­droxy-4-(4-meth­oxy­phen­yl)-4-oxobut-2-enoic acid

3,4-Dihy­droxy-1,6-bis­(4-meth­oxy­phenyl)hexa-2,4-diene-1,6-dione exhibits the di-enol-dione tautomeric form and is compared with its 4-methyl­phenyl analogue. In a potassium salt of 2-hy­droxy-4-(4-meth­oxy­phenyl)-4-oxobut-2-enoic acid, the organic species are linked by a strong hydrogen bond between the carb­oxy­lic acid and carboxyl­ate groups.

Two sodium(I) coordination polymers constructed by the V-shaped ligands 2,2′-[iso­propyl­idene­bis­(1,4-phenyl­ene­oxy)]di­acetic acid and 2,2′-[sulfonyl­bis­(1,4-phenyl­ene­oxy)]di­acetic acid

Two novel inorganic–organic coordination polymers, based on Na^I cations with semi-rigid V-shaped di­carboxyl­ate ligands, have been prepared and structurally characterized.

A fivefold inter­penetrating diamondoid framework constructed by flexible di­pyridyl and di­carboxyl­ate ligands

In a novel three-dimensional Cd^II complex prepared by hydro­thermal assembly of Cd(NO₃)₂·4H₂O, 1,4-bis­[2-(pyridin-4-yl)ethenyl]benzene and 2,2′-(1,4-phenyl­ene)di­acetic acid, each Cd^II centre is located in a distorted penta­gonal bipyramidal coordination environment. The three-dimensional net can be regarded as a diamondoid network by treating the Cd^II atoms as nodes and the benzene and di­acetic acid ligands as linkers.

Synthesis, crystal structure and fluorescence spectrum of a cadmium(II) sulfaquinoxaline complex

A one-dimensional polymeric structure of Cd^II with sulfaquinoxaline is further stabilized by inter­molecular hydrogen bonding. The fluorescence spectrum reveals that the complex emits strong blue fluorescence. The thermal analysis shows that the framework is stable up to 663 K.

Enantio­tropic phase transition in a binuclear tin complex with an O,N,O′-tridentate ligand

A dinuclear tin(IV) complex of 2-[(2-oxido­benzyl­idene)amino]­ethanolate is disordered above 178 K. The crystal structure at 93 K contains two ordered mol­ecules. The phase transition corresponds to an order–disorder transition of a vinyl group bound to the Sn^IV atom.

A novel one-dimensional tubular cadmium(II) coordination polymer based on 5-(carboxyl­atometh­oxy)benzene-1,3-di­carboxyl­ate containing 4-amino­pyridinium ions

A novel anionic tubular Cd^II coordination polymer based on the 5-(carboxyl­atometh­oxy)benzene-1,3-di­carboxyl­ate ligand and containing 4-amino­pyridinium cations had been synthesized under hydro­thermal conditions. In the solid state, the 4-amino­pyridinium cation props up the structure through hydrogen bonds to the O-atom acceptors of ligands and solvent water mol­ecules.

The layered structure of poly[[hexa­aqua­(μ₄-benzene-1,2,4,5-tetra­car­box­ylato)dicopper(II)] tetra­hydrate]

The layered polymeric structure of a benzene-1,2,4,5-tetra­carboxyl­ate–Cu complex forms parallelogram-shaped channels.

Different Zn^II cation coordination geometries in di-μ-acetato-bis­{2-chloro-6-[(pyridine-2-yl­methyl­imino)­methyl]phenol}dizinc(II) chloro­form monosolvate

In a dinuclear zinc(II) complex of acetate and 6-chloro-2-{(E)-[(pyridin-2-yl)methyl­imino]­methyl}phenolate, the Zn^II cations differ in their five-coordinate geometries, with one adopting a distorted trigonal bipyramidal geometry and the other a square-pyramidal geometry.

Multiple anion⋯π inter­actions in tris­(1,10-phenanthroline-κ²N,N′)iron(II) bis­[1,1,3,3-tetra­cyano-2-(2-hy­droxy­ethyl)propenide] mono­hydrate

Double nitrile⋯π interactions are relevant for the crystal packing of charge-diffuse conjugated tetracyanopropenide anions when combined with common heteroaromatic tris-chelate octahedral complexes, [Fe(phen)₃]²⁻.

Low-dimensional compounds containing cyanide groups. XXVI. (Dicyanamido-κN¹)bis­(5,5′-di­methyl-2,2′-bi­pyridine-κ²N,N′)copper(II) complexes with tetra­fluoro­borate and perchlorate anions

The Cu atoms in the title complexes are five-coordinated in distorted trigonal bipyramidal environments by four N atoms of two 5,5′-dimethyl-2,2′-bi­pyridine ligands and one N atom of a dicyanamide anion, which is coordinated in a monodentate manner in the equatorial plane. The structures are stabilized by C—H⋯N and C—H⋯X hydrogen bonds (X = F and O) and π–π inter­actions between pyridine rings.

A well-resolved cyclic water tetra­mer in a dinuclear Cu^II coordination complex based on 1,2-bis­(pyridin-3-yl­­oxy)ethane and capped by pyridine-2,6-di­carb­oxy­lic acid

Two five-coordinated aqua­copper(II) centres chelated to pyridine-2,6-di­carboxyl­ate terminal ligands are bridged by a 1,2-bis­(pyridin-3-yl­oxy)ethane spacer. The structure includes a well-resolved cyclic water tetra­mer, which acts as a subunit to form a larger aggregate.

Bis(4-methyl­anilinium) and bis­(4-iodo­anilinium) penta­molybdates from laboratory X-ray powder data and total energy minimization

The crystal structures of bis­(4-methyl­anilinium) and bis­(4-iodo­anilinium) penta­molybdates were determined using laboratory X-ray data and refined by total energy minimization methods. The obtained structures present alternating organic cation and inorganic polyanion layers bound by weak bonding (apart from ionic inter­actions).

A novel one-dimensional copper(II) coordination polymer and a trinuclear nickel(II) complex with a one-dimensional hydrogen-bonded structure

A novel infinite one-dimensional coordination polymer involving N′-(2-hy­droxy­benzyl­idene)-2-(naphthalen-2-yl­oxy)aceto­hydrazide, and a trinuclear nickel complex of 2-hy­droxy-N′-(2-oxo-2-phen­oxy­ethyl)benzo­hydrazide with a one-dimensional network structure constructed by hydrogen-bonding inter­actions, are reported.

A dense hydrogen-bonding network and an unusually large packing index in tri­aqua­tris­(2,4-dioxo-1,2,3,4-tetra­hydro­pyrimidine-5-carboxyl­ato)neodymium(III) trihydrate

In a mononuclear Nd^III complex, three chelating 2,4-dioxo-1,2,3,4-tetra­hydro­pyrimidine-5-carboxyl­ate ligands and three aqua ligands build up a distorted monocapped square anti­prism around the cation. A complex hydrogen-bonding network results in a densely packed structure (packing index = 77.7%)

A series of N-(2-phenyl­ethyl)nitro­aniline derivatives as precursors for slow and sustained nitric oxide release agents

A series of N-(2-phenyl­ethyl)nitro­aniline derivatives is presented, demonstrating that modest changes in the functional groups cause significant differences in mol­ecular conformation, inter­molecular inter­actions and packing.

Supra­molecular architectures of N-acetyl-L-proline monohydrate and N-benzyl-L-proline

Proline (Pro) exists in its neutral form in N-acetyl-L-proline monohydrate and is zwitterionic in N-benzyl-L-proline. The presence of a water molecule in the neutral form and the difference in the ionization states between the two forms have effected significant changes in the respective intermolecular schemes.

N-[2-(Pyridin-2-yl)ethyl]-derivatives of methane-, benzene- and toluenesulfonamide: prospective ligands for metal coordination

Three N-[2-(pyridin-2-yl)ethyl]-substituted sulfonamides are almost structurally identical, the most dramatic different being seen for the N—C—C—C torsion angle with the introduction of a methyl group in the para position of the sulfonamide moiety. These compounds are prospective ligands for the formation of new metal complexes.

Three new pseudopolymorphs of 6-amino­uracil

The structures of two 6-amino­uracil di­methyl­acetamide monosolvates and a 1-methyl­pyrrolidin-2-one monosolvate display N—H⋯O hydrogen-bonding patterns that link the uracil mol­ecules to their respective solvent mol­ecules. The formation of (8) N—H⋯O hydrogen-bond motifs between 6-amino­uracil mol­ecules can only be found in two-dimensional frameworks, whereas (14) N—H⋯O patterns are present when zigzag chains of 6-amino­uracil mol­ecules are formed.

The glycogen phospho­rylase inhibitor 2-(3-benzyl­amino-2-oxo-1,2-di­hydro­pyridin-1-yl)-N-(3,4-di­chloro­benz­yl)acetamide

The crystal structure of a potent glycogen phospho­rylase a (GPa) inhibitor (IC₅₀ of 6.3 µM) consists of four distinct conjugated π systems separated by rotatable bonds around the Csp³ atoms. The mol­ecules are linked into dimers disposed about a crystallographic centre of symmetry through a cyclic N—H⋯O hydrogen-bonding motif.

Absolute configuration determination of the anti-head-to-head photo­cyclo­dimer of anthracene-2-carb­oxy­lic acid through cocrystallization with L-prolinol

The absolute configuration of the enantio­pure anti-head-to-head cyclo­dimer of anthracene-2-carb­oxy­lic acid was determined. The dimer inter­acts with L-prolinol through a nine-membered hydrogen-bonded ring [(9)], while a di­chloro­methane mol­ecule is incorporated to fill the void space.

A hydrogen-bonded ribbon in 6-amino-3-methyl-5-nitroso-2-(pyrrol­idin-1-yl)pyrimidin-4(3H)-one monohydrate and hydrogen-bonded sheets in 6-amino-2-di­methyl­amino-3-methyl-5-nitroso­pyrimidin-4(3H)-one monohydrate. Corrigendum

Corrigendum to Acta Cryst. (2009), C65, o549–o552.