Polymorph Identification and Crystal Structure Determination by a Combined Crystal Structure Prediction and Transmission Electron Microscopy Approach

Electron diffraction offers advantages over X‐ray based methods for crystal structure determination because it can be applied to sub‐micron sized crystallites, and picogram quantities of material. For molecular organic species, however, crystal structure determination with electron diffraction is hindered by rapid crystal deterioration in the electron beam, limiting the amount of diffraction data that can be collected, and by the effect of dynamical scattering on reflection intensities. Automated electron diffraction tomography provides one possible solution. We demonstrate here, however, an alternative approach in which a set of putative crystal structures of the compound of interest is generated by crystal structure prediction methods and electron diffraction is used to determine which of these putative structures is experimentally observed. This approach enables the advantages of electron diffraction to be exploited, while avoiding the need to obtain large amounts of diffraction data or accurate reflection intensities. We demonstrate the application of the methodology to the pharmaceutical compounds paracetamol, scyllo‐inositol and theophylline.     

New Approaches for Solving Crystal Structures from Powder Diffraction Data

The determination of crystal structures from single crystal diffraction data can generally be carried out routinely and straightforwardly. However, many crystalline solids can be obtained only as microcrystalline powders and are not suitable for investigation by conventional single crystal diffraction methods. In the past, this problem has limited the ability to elucidate the structural properties of such materials. For the wide range of materials in this category, there is clearly a pressing need to develop and exploit techniques that allow crystal structures to be solved from powder diffraction data. Although traditional techniques for structure solution from powder diffraction data have been applied successfully in several cases, these techniques have certain intrinsic limitations, and for the case of organic molecular crystals the challenges that must be overcome are particularly severe. For these reasons, our recent research has focused on the development and implementation of new methodologies for structure solution from powder diffraction data, leading to new “direct-space” techniques for structure solution in which a hypersurface based on the profile R-factor is searched using Monte Carlo or Genetic Algorithm techniques. This paper presents a brief overview of the problems and challenges associated with structure solution from powder diffraction data. The foundations of the techniques that we have developed are described, and illustrative examples (from the field of organic molecular crystals) are given to highlight the application of these techniques.     

Microcrystal Electron Diffraction (MicroED) for Small‐Molecule Structure Determination

The development of new methods to analyze and determine molecular structures parallels the ability to accelerate synthetic research. For many decades, single‐crystal analysis by X‐ray diffraction (SXRD) has been the definitive tool for structural analysis at the atomic level; the drawback, however, is that a suitable single crystal of the analyte needs to be grown. The recent innovation of the crystalline sponge (CS) method allows the microanalysis of compounds simply soaked in a readily prepared CS crystal, thus circumventing the need to screen crystallization conditions while also using only a trace amount of the sample. In this context, electron diffraction for the structure determination of small molecules is discussed as potentially the next big development in this field.     

Metergoline II: structure solution from powder diffraction data with preferred orientation and from microcrystal

Metergoline is a dopamine agonist and serotonin antagonist used both in human and veterinary medicine. In addition to the previously known crystalline form, a new polymorph, which crystallizes from aqueous solution, was found. Since it was initially impossible to prepare a single crystal of quality suitable for single crystal X-ray diffraction measurements using a conventional laboratory source, the structure was solved from the powder diffraction data using synchrotron radiation. The structure determination also included solving the effects of preferred orientation. Characterization was simultaneously done by solid-state NMR spectroscopy. Finally, a small single crystal suitable for synchrotron diffraction was found after numerous tries. Crystal structure determination using this single crystal confirmed the powder-based solution. Comparison of information obtained by different experimental methods (powder diffraction, ssNMR, single crystal diffraction) was made.     

X射线晶体学结合电子晶体学在复杂无机晶体结构解析中的应用

自然界中的材料,比如无机材料,有机材料,生物材料等等,均有其独特的物理和化学性质。而材料的性能又与材料的结构息息相关,只有充分了解了材料的结构,才能更加深入的研究材料性质。因此,材料结构的确定在化学、物理、生物等学科中的显得尤为重要。X射线晶体学作为传统的结构解析技术仍然是目前最重要的结构解析手段,但是对于复杂结构,X射线衍射晶体学解析结构也存在一些不足,往往需要其他技术手段相补充才能完成复杂结构的结构解析。电子晶体学虽然起步比X射线晶体学晚,但是,经过近几十年的发展,已经是结构解析领域一个非常重要的手段。本文将主要介绍X射线晶体学结合电子晶体学在复杂无机晶体结构解析中的应用。     

Structure determination from powder diffraction

The review surveys modern methods for the determination of unknown crystal structures of organic and inorganic compounds from powder diffraction data. The main stages of this process, from the preparation of the specimen to a search for the structural motif followed by the Rietveld refinement, are considered. The results obtained on different diffractometers using X-ray, synchrotron, and neutron radiations are demonstrated to be well reproducible. Examples of successful structure solution are cited, which provide evidence that powder diffraction is a reliable tool in establishing structures of a wide range of compounds for which single crystals are unavailable.     

N-(1-萘基)-琥珀酰亚胺化合物晶体结构的理论预测

用Materials Studio软件对N-(1-萘基)-琥珀酰亚胺多晶粉末的X射线衍射数据进行衍射峰指标化、晶胞参数优化和空间群搜索等理论计算, 可以确定晶体结构所属的晶系和空间群, 并初步给出和多晶粉末衍射数据相近的晶胞参数; 在已确定空间群范围内, 以密度泛函理论计算得到的最低能量构象作为初始分子结构, 对N-(1-萘基)-琥珀酰亚胺多晶进行晶体结构理论预测, 给出一系列假定的晶胞参数, 从中可以找到和经上述计算给出的晶胞参数一致的晶体结构；对其进行晶胞参数优化后, 得到晶体结构具有和多晶粉末X射线衍射数据相近的衍射曲线, 并与已有的单晶数据相吻合.     

Physico-chemical characterization of an active pharmaceutical ingredient

The physico-chemical properties and polymorphism of a new active pharmaceutical ingredient entity has been analyzed and the gain of knowledge during the chemical development of the substance is described. Initial crystallization revealed an anhydrous crystal form with good crystallinity and a single, sharp DSC melting peak at 171°C and a straightforward development of this crystal form seemed possible. However, during polymorphism screening, new crystalline forms were detected that were often analyzed as mixtures of crystal forms. The process of characterization and identification of the different crystalline forms and its thermodynamical relationship has been supported by a combination of experimental and computational work including determination of the three-dimensional structures of the crystal forms. The crystal structure of one polymorphic form was solved by single crystal X-ray structure analysis. Unfortunately, Mod B resisted in formation of suitable single crystals, but its structure could be solved by high resolution powder diffraction data analysis using synchrotron radiation. Calculation of the theoretical X-ray powder diffraction pattern from three dimensional crystal coordinates allowed an unambiguous identification of the different crystalline forms. Two polymorphic crystal forms of the API-CG3, named Mod A and Mod B, are enantiotropic whereas Mod B is the most stable polymorph at room temperature up to about 50°C and Mod A at temperatures above 50°C. The mechanism of the solid-solid transition can be explained by analyzing the molecular packing information gained from the single crystal structures. A third crystalline form with the highest melting peak turned out to be not a polymorphic or pseudopolymorphic crystal modification of our API-CG3 but a chemically different substance. This revised version was published online in July 2006 with corrections to the Cover Date.     

Determination of the Crystal Structure of a New Polymorph of Theophylline

A new approach to crystal structure determination, combining crystal structure prediction and transmission electron microscopy, was used to identify a potential new crystal phase of the pharmaceutical compound theophylline. The crystal structure was determined despite the new polymorph occurring as a minor component in a mixture with Form II of theophylline, at a concentration below the limits of detection of analytical methods routinely used for pharmaceutical characterisation. Detection and characterisation of crystallites of this new form were achieved with transmission electron microscopy, exploiting the combination of high magnification imaging and electron diffraction measurements. A plausible crystal structure was identified by indexing experimental electron‐diffraction patterns from a single crystallite of the new polymorph against a reference set of putative crystal structures of theophylline generated by global lattice energy minimisation calculations.     

Gas Electron Diffraction and its Influence on the Solution of the Phase Problem in Crystal Structure Determination

We studied, and performed research for our Ph.D. degrees in the area of gas electron diffraction. Our mentor was Lawrence Brockway. a pioneer in this subject. At that time, research in gas electron diffraction was in its early stages of development. In 1941, the distinguished Peter Debye wrote a theoretical paper concerning gas electron diffraction which challenged ones capability to develop the necessary experimental equipment and to further advance the theoretical developments so as to greatly extend the science of gas electron diffraction. We carried these thoughts in mind when we joined the Naval Research Laboratory, where the opportunity to design and produce excellent equipment was readily available. In the course of pursuing this research area, one of the findings was the existence of non-negativity as a condition for the results of a diffraction experiment for gaseous substances. When we became interested in the field of crystal structure determination, the familiarity with non-negativity which was needed in the study of gases, led to a search for the necessary and sufficient condition for a Fourier series to be non-negative. The search was successful and has played an important part in crystal structure determination. Some early applications to complicated structures are described.     

How to determine structures when single crystals cannot be grown: opportunities for structure determination of molecular materials using powder diffraction data

Many crystalline solids cannot be prepared as single crystals of sufficient size and/or quality for structure determination to be carried out using single crystal X-ray diffraction techniques. In such cases, when only polycrystalline powders of a material are available, it is necessary instead to tackle structure determination using powder X-ray diffraction. This article highlights recent developments in the opportunities for determining crystal structures directly from powder diffraction data, focusing on the case of molecular solids and giving particular attention to the most challenging stage of the structure determination process, namely the structure solution stage. In particular, the direct-space strategy for structure solution is highlighted, as this approach has opened up new opportunities for the structure determination of molecular solids. The article gives an overview of the current state-of-the-art in structure determination of molecular solids from powder diffraction data. Relevant fundamental aspects of the techniques in this field are described, and examples are given to highlight the application of these techniques to determine crystal structures of molecular materials.     

X-ray and neutron powder diffraction study of the double perovskites Ba2LnSbO6 (Ln=La, Pr, Nd and Sm)

The crystal structures of Ba₂LnSbO₆ (Ln=La, Pr, Nd and Sm) at room temperature have been investigated by profile analysis of the Rietveld method using either combined X-ray and neutron powder diffraction data or X-ray powder diffraction data. It has been shown that the structure of Ba₂LnSbO₆ with Ln =La, Pr and Nd are neither monoclinic nor cubic as were previously reported. They are rhombohedral with the space group . The distortion from cubic symmetry is due to the rotation of the LnO₆/SbO₆ octahedra about the primitive cubic [111]_p-axis. On the other hand, the structure of Ba₂SmSbO₆ is found to be cubic. All compounds contain an ordered arrangement of LnO₆ and SbO₆ octahedra.     

Syntheses，Structures and Properties of Some New Composition Perovskite Compounds：Sr_（0．6）Bi_（0．4）FeO_（2．7），Sr_（1－x）Bi_xFeO_（3－y） and Ba_（1．5）Pt_（0．5）Mn_2O_6

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Crystal structure of Ca2Ln3Sb3O14 (Ln=La, Pr, Nd and Y): A novel variant of weberite

The crystal structures of Ca₂Ln₃Sb₃O₁₄ (Ln=La, Pr, Nd and Y) and Ca₂Sb₂O₇ at room temperature were refined by the Rietveld method using combined X-ray and neutron powder diffraction data. Ca₂Sb₂O₇ adopts the weberite structure having the space group Imma. The structures of Ca₂Ln₃Sb₃O₁₄ are, however, neither the orthorhombic nor the tetragonal chiolite as has been suggested previously. They crystallize in the monoclinic space group I2/m11 belonging to a hitherto unknown type of deformation of the parent (orthorhombic) weberite structure.     

Crystal and molecular structure of N-(trifluorosilylmethyl)glutarimide. Unusual planar configration of the pseudosaturated six-membered heterocycle

The crystal and molecular structure of N-(trifluorosilylmethyl)glutarimide has been determined by X-ray diffraction. The independent part of the unit cell of the single crystal contains two molecules that differ in the conformation of the glutarimide heterocycle. The coordination polyhedron of the silicon atom in them is a trigonal bipyramid. The bond lengths and angles in these molecules are compared with those in the crystal structures of related compounds.     

Comparative structural analysis of a histone-like protein from Spiroplasma melliferum in the crystalline state and in solution

A solution of a histone-like protein from Spiroplasma melliferum (HUSpm) was examined by small-angle X-ray scattering (SAXS). The experimental SAXS curve was compared with those calculated for the HUSpm structures from the PDB databank obtained by both X-ray diffraction analysis and nuclear magnetic resonance spectroscopy. The model of the HUSpm structure in solution, which best agrees with the experimental SAXS data, has a shorter distance between the centers of mass of the HUSpm monomers compared to the crystal structure, indicating that the HUSpm monomers can be located closer to each other in solution than in the crystalline state.     

Host Perturbation in a β‐Hydroquinone Clathrate Studied by Combined X‐ray/Neutron Charge‐Density Analysis: Implications for Molecular Inclusion in Supramolecular Entities

X‐ray/neutron (X/N) diffraction data measured at very low temperature (15 K) in conjunction with ab initio theoretical calculations were used to model the crystal charge density (CD) of the host–guest complex of hydroquinone (HQ) and acetonitrile. Due to pseudosymmetry, information about the ordering of the acetonitrile molecules within the HQ cavities is present only in almost extinct, very weak diffraction data, which cannot be measured with sufficient accuracy even by using the brightest X‐ray and neutron sources available, and the CD model of the guest molecule was ultimately based on theoretical calculations. On the other hand, the CD of the HQ host structure is well determined by the experimental data. The neutron diffraction data provide hydrogen anisotropic thermal parameters and positions, which are important to obtain a reliable CD for this light‐atom‐only crystal. Atomic displacement parameters obtained independently from the X‐ray and neutron diffraction data show excellent agreement with a |ΔU| value of 0.00058 Ų indicating outstanding data quality. The CD and especially the derived electrostatic properties clearly reveal increased polarization of the HQ molecules in the host–guest complex compared with the HQ molecules in the empty HQ apohost crystal structure. It was found that the origin of the increased polarization is inclusion of the acetonitrile molecule, whereas the change in geometry of the HQ host structure following inclusion of the guest has very little effect on the electrostatic potential. The fact that guest inclusion has a profound effect on the electrostatic potential suggests that nonpolarizable force fields may be unsuitable for molecular dynamics simulations of host–guest interaction (e.g., in protein–drug complexes), at least for polar molecules.     

Development of a multipopulation parallel genetic algorithm for structure solution from powder diffraction data

Previously, the genetic algorithm (GA) approach for direct-space crystal structure solution from powder diffraction data has been applied successfully in the structure determination of a range of organic molecular materials. In this article, we present a further development of our approach, namely a multipopulation parallel GA (PGA), which is shown to give rise to increased speed, efficiency, and reliability of structure solution calculations, as well as providing new opportunities for further optimizing our GA methodology. The multipopulation PGA is based on the independent evolution of different subpopulations, with occasional interaction (e.g., transfer of structures) allowed to occur between the different subpopulations. Different strategies for carrying out this interpopulation communication are considered in this article, and comparisons are made to the conventional single-population GA. The increased power offered by the PGA approach creates the opportunity for structure determination of molecular crystals of increasing complexity.     

The low‐temperature form of calcium gold stannide,CaAuSn

The EuAuGe‐type CaAuSn phase has been synthesized and single‐crystal X‐ray diffraction analysis reveals that it has an orthorhombic symmetry (space group Imm2), with a = 4.5261 (7) Å, b = 7.1356 (11) Å and c = 7.8147 (11) Å. The structure features puckered layers that are connected by homoatomic Au—Au and Sn—Sn interlayer bonds. This structure is one of the two parent structures of its high‐temperature polymorph (ca 873 K), which is an intergrowth structure of the EuAuGe‐ and SrMgSi‐type structures in a 2:3 ratio.