High Temperature Electron Diffraction on Organic Crystals: In Situ Crystal Structure Determination of Pigment Orange 34.

Small molecule structures and their applications rely on good knowledge of their atomic arrangements. However, the crystal structures of these compounds and materials, which are often composed of fine crystalline domains, cannot be determined with single-crystal X-ray diffraction. Three-dimensional electron diffraction (3D ED) is already becoming a reliable method for the structure analysis of submicrometer-sized organic materials. The reduction of electron beam damage is essential for successful structure determination and often prevents the analysis of organic materials at room temperature, not to mention high temperature studies. In this work, we apply advanced 3D ED methods at different temperatures enabling the accurate structure determination of two phases of Pigment Orange 34 (C34H28N8O2Cl2), a biphenyl pyrazolone pigment that has been industrially produced for more than 80 years and used for plastics application. The crystal structure of the high-temperature phase, which can be formed during plastic coloration, was determined at 220 °C. For the first time, we were able to observe a reversible phase transition in an industrial organic pigment in the solid state, even with atomic resolution, despite crystallites being submicrometer in size. By localizing hydrogen atoms, we were even able to detect the tautomeric state of the molecules at different temperatures. This demonstrates that precise, fast, and low-dose 3D ED measurements enable high-temperature studies the door for general in situ studies of nanocrystalline materials at the atomic level.

Solid-State NMR-Driven Crystal Structure Prediction of Molecular Crystals: The Case of Mebendazole.

Among all possible NMR crystallography approaches for crystal-structure determination, crystal structure prediction - NMR crystallography (CSP-NMRX) has recently turned out to be a powerful method. In the latter, the original procedure exploited solid-state NMR (SSNMR) information during the final steps of the prediction. In particular, it used the comparison of computed and experimental chemical shifts for the selection of the correct crystal packing. Still, the prediction procedure, generally carried out with DFT methods, may require important computational resources and be quite time-consuming, especially if there are no available constraints to use at the initial stage. Herein, the successful application of this combined prediction method, which exploits NMR information also in the input step to reduce the search space of the predictive algorithm, is presented. Herein, this method was applied on mebendazole, which is characterized by desmotropism. The use of SSNMR data as constraints for the selection of the right tautomer and the determination of the number of independent molecules in the unit cell led to a considerably faster process, reducing the number of calculations to be performed. In this way, the crystal packing was successfully predicted for the three known phases of mebendazole. To evaluate the quality of the predicted structures, these were compared to the experimental ones. The crystal structure of phase B of mebendazole, in particular, was determined de novo by powder diffraction and is presented for the first time in this paper.

Sustained-release hot melt extrudates of the weak acid TMP-001: A case study using PBB modelling.

Over the last 30 years, hot melt extrusion has become a leading technology in the manufacture of amorphous drug delivery systems. Mostly applied as an 'enabling formulation' for poorly soluble compounds, application in the design of sustained-release formulations increasingly attracts the attention of the pharmaceutical industry. The drug candidate TMP-001 is currently under evaluation for the early treatment of Multiple Sclerosis. Although this weak acid falls into class II of the Biopharmaceutics Classification System, the compound exhibits high solubility in the upper intestine resulting in high peroral bioavailability. In the present studies, four different formulation prototypes varying in their sustained-release behavior were developed, using L-arginine as a pore-forming agent in concentrations ranging between 0 and 20%. Initially, biorelevant release testing was applied to assess the dissolution behavior of the prototypes. For these formulations, a total drug release of 44.7%, 64.6%, 75%, and 90.5% was achieved in FaSSIF-v2 after 24 h. Two candidates were selected for further characterization considering the crystal structure and the physical stability of the amorphous state of TMP-001 in the formulations together with the release behavior in Level II biorelevant media. Our findings indicate L-arginine as a valuable excipient in the formulation of hot melt extrudates, as its presence led to a considerable stabilization of the amorphous state and favorably impacted the milling process and release behavior of TMP-001. To properly evaluate the proposed formulations and the importance of colonic dissolution and absorption on the overall bioavailability, a physiologically-based biopharmaceutics model was used.

Crystal structures of ordered and plastic-crystalline phases of iso-butyllithium by X-ray powder diffraction.

Donor-unsupported iso-butyllithium consists of hexamers with an ordered triclinic structure at -80 °C (α-phase). At ambient temperature, the compound exists as an orthorhombic, remarkably stable, plastic-crystalline γ-phase, which is built by disordered hexamers adopting a distorted face-centred cubic packing. Both structures were determined by X-ray powder diffraction. Additionally, an intermediate ß-phase is observed.

Syntheses and Crystal Structures of Phenyl-Lithium Derivatives.

Although organolithium compounds have been studied and applied for ∼100 years, only few crystal structures of pure, unsolvated organolithium compounds have been reported so far. Therefore, several phenyl-lithium derivatives were synthesized by lithium-halogen exchange reactions, yielding fairly soluble polymers in the cases of 4- and 2-methylphenyl-lithium ( p-TolLi and o-TolLi). Their crystal structures have been determined by X-ray powder diffraction. Remarkably, o-TolLi crystallizes in the noncentrosymmetric space group P212121 with two independent monomers, whereas the crystal structure of p-TolLi is described in spacegroup P21/ a. In contrast, no polymer of 5- m-XyLi (3,5-dimethyl-phenyl-lithium) could be observed, but single crystals of a [(5- m-XyLi)3(MTBE)3LiBr] adduct were isolated (MTBE = methyl- tert-butylether). This gives hints on the nature of lithium-halogen exchange reactions. Steric and electronic effects of the phenyl-lithium substitution are further discussed in conjunction with related compounds.

Influence of the co-ligand on the magnetic and relaxation properties of layered cobalt(II) thiocyanato coordination polymers.

Reaction of Co(NCS)2 with 1,2-bis(4-pyridyl)-ethane (bpa) leads to the formation of [Co(NCS)2(bpa)2]n, which, on heating, transforms into the new layered coordination polymer [Co(NCS)2(bpa)]n. This compound can also be prepared in solution, but because no reasonable single crystals are available, its crystal structure was determined from X-ray powder data from scratch. In the crystal structure of [Co(NCS)2(bpa)]n, the cobalt(II) cations are coordinated by two S-bonded and two N-bonded thiocyanato anions and two N atoms of the bpa co-ligands in a distorted octahedral geometry. The cobalt(II) cations are linked into chains by pairs of µ-1,3 bridging thiocyanato anions. These chains are further connected into layers by the 1,2-bis(4-pyridyl)-ethane ligand. The compound was magnetically characterized, and, for comparative purposes, the complementary magnetic study of a known and very similar compound, [Co(NCS)2(bpe)]n (bpe = 1,2-bis(4-pyridyl)-ethylene), was also undertaken. The compounds differ in their interchain interactions, which are antiferromagnetic but significantly greater for [Co(NCS)2(bpe)]n. Magnetic measurements indicate that [Co(NCS)2(bpa)]n is a canted antiferromagnet with Néel temperature TN = 3.1 K and that Co(NCS)2(bpe) is an antiferromagnet with TN = 4.0 K. Both compounds show a metamagnetic transition with a critical field HC ∼ 40 Oe and ∼ 400 Oe, respectively. Magnetic relaxations were studied by means of dc and ac methods and analyzed using the Argand diagrams. Except for the thermally activated single chain and domain wall relaxations observed for both compounds, temperature-independent slow relaxations were observed for [Co(NCS)2(bpa)]n.

Structural properties of so-called NSAID-phospholipid-complexes.

So-called NSAID-phospholipid-complexes have been recently reported in literature to reduce local gastrointestinal toxicity. The present work was dedicated to the structural characterization of so-called drug-phospholipid-complexes on the example of diclofenac sodium, ibuprofen and piroxicam complexes with dipalmitoylphosphatidylcholine (DPPC) at different stages of preparation. The applied techniques include (1)H/2D ROESY NMR for the structural characterization in organic solvents, FT-IR and X-ray diffraction for the structural characterization in the solid state and PCS, (31)P NMR, as well as MAS (1)H/2D NOESY NMR for the structural characterization in aqueous media following hydration. Whereas the formation of isolated 1:1 drug-phospholipid-complexes with a preferential location of diclofenac and ibuprofen at the polar head group, stabilized by cation-π interaction, seems reasonable in organic solvents, it was found that mainly liposomal and micellar structures are formed upon hydration of the drug-phospholipid-complexes. Hence the term "NSAID-phospholipid-complex" may be misleading in the context with physiologically relevant aqueous media. Piroxicam did not show significant interaction with DPPC.

Predicted and experimental crystal structures of ethyl-tert-butyl ether.

Possible crystal structures of ethyl-tert-butyl ether (ETBE) were predicted by global lattice-energy minimizations using the force-field approach. 33 structures were found within an energy range of 2 kJmol(-1) above the global minimum. Low-temperature crystallization experiments were carried out at 80-160 K. The crystal structure was determined from X-ray powder data. ETBE crystallizes in C2/m, Z = 4, with molecules on mirror planes. The ETBE molecule adopts a trans conformation with a (CH(3))(3)C-O-C-C torsion angle of 180°. The experimental structure corresponds with high accuracy to the predicted structure with energy rank 2, which has an energy of 0.54 kJmol(-1) above the global minimum and is the most dense low-energy structure. In some crystallization experiments a second polymorph was observed, but the quality of the powder data did not allow the determination of the crystal structure. Possibilities and limitations are discussed for solving crystal structures from powder diffraction data by real-space methods and lattice-energy minimizations.

Solvent-free mesityllithium: solid-state structure and its reactivity towards white phosphorus.

The donor-free mesityllithium was prepared from the reaction of MesBr with n-BuLi in diethyl ether at -78 degrees C. The solid-state structure of unsupported mesityllithium consists of C(2)Li(2)-rings composed of two LiMes units, which interact with adjacent dimers [LiMes](2), forming a polymeric infinite chain along the crystallographic c-axis (monoclinic space group, P2(1)/n). The structure of donor-free mesityllithium reveals short contacts between the C atoms of the mesityl rings and the lithium atoms of neighbouring [LiMes](2) units. The structure determination of LiMes was performed by X-ray powder diffraction. In addition we have investigated the reaction of LiMes with Me(3)SnCl and P(4) for our understanding of the reactivity of donor-free mesityllithium. The heterogeneous reaction of donor-free mesityllithium with Me(3)SnCl produces conveniently the stannylated mesitylene Me(3)SnMes (triclinic, space group P1). White phosphorus reacts with three equivalents of unsupported mesityllithium in benzene to give Li(3)P(4)Mes(3). In this context it should be noted that a tetraphosphide with an identical LiP-core as in Li(3)P(4)Mes(3) had been formed in the 1:3 reaction of P(4) with the silanide Li[SitBu(3)]. The tetraphosphide Li(3)P(4)Mes(3) was analyzed using X-ray crystallography (monoclinic, space group C2/c).

Predicted crystal structures of tetramethylsilane and tetramethylgermane and an experimental low-temperature structure of tetramethylsilane.

No crystal structure at ambient pressure is known for tetramethylsilane, Si(CH(3))(4), which is used as a standard in NMR spectroscopy. Possible crystal structures were predicted by global lattice-energy minimizations using force-field methods. The lowest-energy structure corresponds to the high-pressure room-temperature phase (Pa3, Z = 8). Low-temperature crystallization at 100 K resulted in a single crystal, and its crystal structure has been determined. The structure corresponds to the predicted structure with the second lowest energy rank. In X-ray powder analyses this is the only observed phase between 80 and 159 K. For tetramethylgermane, Ge(CH(3))(4), no experimental crystal structure is known. Global lattice-energy minimizations resulted in 47 possible crystal structures within an energy range of 5 kJ mol(-1). The lowest-energy structure was found in Pa3, Z = 8.

catena-Poly[[dipyridine-nickel(II)]-trans-di-µ-chlorido] from powder data.

The asymetric unit of the title compound, [NiCl(2)(C(5)H(5)N)(2)](n), contains two Ni(II) ions located on different twofold rotational axes, two chloride anions and two pyridine rings in general positions. Each Ni(II) ion is coordinated by two pyridine rings, which form dihedral angles of 33.0 (2) and 11.0 (2)° for the two centers, and four chloride anions in a distorted octa-hedral geometry. The chloride anions bridge Ni(II) ions related by translation along the short b axes into two crystallographically independent polymeric chains.

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.

Magnetic properties of two double-layer structures built from hydroxynaphthoic acids and manganese.

Double-layer structures consisting of alternating polar and non-polar layers have been prepared using Mn2+ ions and o-hydroxynaphthoic acids. The polar layers contain the Mn2+ ions, carboxylate groups, hydroxy groups and water molecules. The non-polar layers are built up from the naphthalene moieties. In catena-poly[[diaquamanganese(II)]bis(mu-3-hydroxy-2-naphthoato-kappa2O:O')] (also called manganese 3-hydroxy-2-naphthoate dihydrate), [Mn(C11H7O3)2(H2O)2]n, (I), the Mn2+ ions are connected by carboxylate groups to form two-dimensional networks. This compound shows distinct antiferromagnetic interactions and long-range ordering at low temperature. In contrast, tetraaquabis(1-hydroxy-2-naphthoato-kappaO)manganese(II), [Mn(C11H7O3)2(H2O)4], (II), which lacks a close linkage between the Mn2+ ions, reveals purely paramagnetic behaviour. In (II), the Mn2+ ion lies on an inversion centre.

Determination of the physical state of norethindrone acetate containing transdermal drug delivery systems by isothermal microcalorimetry, X-ray diffraction, and optical microscopy.

Transdermal drug delivery systems (TDDS) enable a controlled drug delivery to the skin. The low permeability of the stratum corneum necessitates a high drug concentration of the polymeric matrix and often requires supersaturation. This, however, promotes crystallisation of supersaturated systems. Isothermal microcalorimetry at 25 degrees C, polarisation light microscopy, and X-ray powder diffraction (XRPD) were used to characterise the crystal growth of norethindrone acetate (NEA). The solubility of NEA in the patches determined by these methods is about 4%. The crystallisation process could be measured reliably and with a high accuracy by microcalorimetry and microscopy. XRPD was considerably less sensitive but was the only method allowing a semi-quantitative determination of the amounts of crystals formed. The drug-associated heat measured by microcalorimetry increased proportionally with increasing NEA concentration in the concentration range of 4-10% demonstrating a constant crystallisation rate. At a higher supersaturation, such as 12% drug content, the crystallisation process was accelerated. The application of Johnson-Mehl-Avrami kinetics for the analysis of nucleation and crystal growth of the punched patches indicated a site-saturated nucleation mechanism and a one-dimensional crystal growth. The crystallisation enthalpy of NEA was -22.8+/-2.6 kJ/mol. The most specific method to observe the crystal formation is polarisation light microscopy. However, the microscopic analysis requires much longer storage times than microcalorimetry to detect crystallisation.

Use of isothermal heat conduction microcalorimetry, X-ray diffraction, and optical microscopy for characterisation of crystals grown in steroid combination-containing transdermal drug delivery systems.

The combined application of the steroids estradiol (E2) hemihydrate and norethindrone acetate (NEA) is desirable for hormone replacement therapy. Transdermal drug delivery systems (TDDS) enable a controlled delivery of these drugs to the skin. However, in order to attain high skin permeation rates the concentration of the dissolved drugs in the TDDSs has to be high. This often results in supersaturated systems with a high crystallisation tendency. The combination of NEA and E2-hemihydrate in the acrylic matrix of patches yields crystals that are different from single drug systems. A new crystal phase showing additional X-ray powder diffraction peaks and a new feather-like crystal shape appeared. The crystal formation was considerably accelerated and enhanced by increasing E2 contents in the patches. The new crystal phase seems to be kinetically favoured compared with crystals appearing from pure E2-hemihydrate or NEA. A crystallisation enthalpy of -7.9+/-0.95 kJ/mol in the matrix containing a 1:3 mixture of E2-hemihydrate and NEA was determined by isothermal microcalorimetry. The crystallisation rate increased with higher drug concentrations. In addition, the influence of patch pre-treatment at 80 degrees C prior to storage on crystallisation was investigated. This treatment enabled a slight reduction of the crystallisation in the TDDSs. Microcalorimetry enabled the classification of various additives according to their influence on the crystallisation process.

Crystallisation of estradiol containing TDDS determined by isothermal microcalorimetry, X-ray diffraction, and optical microscopy.

Transdermal drug delivery systems (TDDS) enable a controlled delivery of drugs to the skin. However, it is still a problem to achieve a stable and prolonged constant drug release. To attain high permeation rates across the skin, the concentrations of the drug dissolved have to be high and often create supersaturated, thermodynamically metastable, or unstable systems that possess a high tendency to crystallise. In the present study, microcalorimetry as well as polarisation microscopy and X-ray powder diffraction (XRPD) were used to characterise the growing crystal germs of estradiol (E2) hemihydrate. Polarisation microscopy enabled the observation of crystals with two different morphologies of E2 in the polymeric acrylic transdermal patch matrix. Crystal formation and growth were also detected by XRPD. The diffraction pattern corresponded to estradiol hemihydrate. The intensity of the observed reflections was proportional to the crystal quantities and increased during storage. A high supersaturation resulted in high peak intensities caused by a high crystallisation rate. Since precipitation is generally accompanied by heat evolution, crystal germ formation, and crystal growth could easily be detected early by isothermal microcalorimetry. Much lower amounts of crystal were detected by this method than with the significantly less sensitive XRPD method. Microscopy was equally sensitive to but much more time-consuming than microcalorimetry.