Papers by STAVROS NICOLOPOULOS
Microscopy and Microanalysis, Jul 22, 2023
Microscopy and Microanalysis, Aug 1, 2019
Acta Crystallographica, Aug 22, 2018
Acta Crystallographica, Dec 1, 2017
Polymorphism plays a vital role in the development of pharmaceutical ingredients. Polymorphs of a... more Polymorphism plays a vital role in the development of pharmaceutical ingredients. Polymorphs of active pharmaceutical ingredients (APIs) have always drawn attention in view of their physicochemical and intellectual property. Sofosbuvir (commercially marketed as Sovaldi by Gilead Sciences, USA) is one of the best-known and most prescribed drug for chronic hepatitis C, genotypes 1, 2, 3, 4, 5, and 6, usually in combination with other medications depending on the specific genotype. Sofosbuvir is a prodrug that is metabolized to the active antiviral agent 2'-deoxy-2'-α-fluoro-β-C-methyluridine-5'-monophosphate. It is a high revenue API ($24.9 billion in 2014) since was first commercialized in 2013. Sofosbuvir is known to exhibit polymorphism[1] and till date more than 15 polymorphs including amorphous form are reported. Gilead Sciences reported[1a-1c] eight crystalline polymorphs, 4 anhydrous forms (designated as Form 1, Form 6, Form 7 and Form 8) and 4 unstable solvates of Sofosbuvir. The four anhydrous forms showed varying melting points in the range of 100 to 140°C. Recently Qi et al [1k] reported thermodynamic relationships of Sofosbuvir polymorphs by thermal analysis and solubility extrapolation and confirms that form 6 and Form 7 are enantiotropic in nature while form 1 is monotropic in nature with form 6 and form 7. However, till date no report on crystal structures of Sofosbuvir polymorphs were known in literature. We report here for the first time crystal structure analysis of Sofosbuvir polymorphs Form1, Form 7 and Form 8. Form 1 and form 7 are crystallizes in monoclinic crystal (P21) system while form 8 get crystallized into orthorhombic crystal system with non-centrosymmetric space group P212121. The crystal structure analysis reveals Sofosbuvir exhibits conformational polymorphism. Conformational flexibility around phosphate group leads to different types of hydrogen bonding networks dominated by N-H…O, O-H…O, C-H…O interactions. Further, the inability to grow the single crystals of Form 6 suitable for single crystal X-ray diffraction made us to explore 3D precession electron diffraction tomography[2] and rietveld method[3] for deriving the crystal structure. In this work we discuss for the first time, structural features of Sofosbuvir polymorphs and application of electron diffraction technique for crystal structure determination of Form 6.
Bulletin of the American Physical Society, Mar 17, 2010
An automated technique for the crystal phase and orientation mapping of polycrystalline materials... more An automated technique for the crystal phase and orientation mapping of polycrystalline materials in a transmission electron microscope has been developed [1]. This technique is based on template matching of experimental electron diffraction spot patterns to their pre-calculated theoretical counterparts. Precession of the primary electron beam around the optical axis of the microscope during the recording of the diffraction patterns improves the reliability of this technique significantly. Promising results have so far been obtained with this technique for precipitates in heavily deformed austenitic stainless steels [1] and ensembles of iron-oxide nanocrystals [2].
Microscopy and Microanalysis, Jul 1, 2009
Three novel strategies for the structurally identification of nanocrystals in a Transmission Elec... more Three novel strategies for the structurally identification of nanocrystals in a Transmission Electron Microscope (TEM) are presented [1]. Either a single High-Resolution Transmission Electron Microscopy (HRTEM) image [2] or a single Precession Electron Diffractogram (PED) [3] can be employed. The structural identification information is in both cases collected from an individual nanocrystal. PED from fine-grained crystal powders may also be utilized. Automation of the former two strategies shall lead to statistically significant results on ensembles of nanocrystals. The structural information that can be extracted from a HRTEM image of an approximately 5 to 10 nm thick nanocrystal is the projected reciprocal lattice geometry, the 2D symmetry, and a few structure factor amplitudes and phase angles. While the structure factor amplitudes suffer from dynamical diffraction effects and are in addition modified by the (not precisely known) contrast-transfer function of the objective lens, the structure factor phase angles are remarkably stable against dynamical diffraction effects and slight crystal misorientations.
Journal of Archaeological Science: Reports
colour, recovered from the Palace Complex of Mystras in southern Peloponnese, Greece. Their date ... more colour, recovered from the Palace Complex of Mystras in southern Peloponnese, Greece. Their date cannot be determined with specificity but has to span between the mid-13th and mid-19th c. AD, the period since the construction of the site and throughout its continuous use as the administrative centre of the Despotate of Mystras. The extremely rare occurrence of opaque glass vessels of this period in Greece, as well as the recovery of most samples within Building E of the Complex, suggest that the samples were precious objects, possibly owned by high ranking members of the Palace. A multi-technique approach, including Optical microscopy, SEM/EDS, Raman spectroscopy and TEM analysis, was implemented in order to determine the microstructure and raw materials of the samples. Despite the small number of samples, a remarkable variability was revealed in terms of the raw materials and manufacturing processes employed. Overall, three different opacification techniques were documented among the white and grey/blue samples: The Na-rich glasses were opacified using either cassiterite, a typical opacifier for the period, or calcium antimonate, a less common opacifier in the post-Medieval glassmaking. The K-rich white glasses were opacified with the addition of the ashes of animal bones, as suggested by the presence of calcium phosphates, a Byzantine tradition that was possibly also used by Bohemian glassmakers. Finally, the red glasses present certain atypical traits in their microstructure and chemical composition. The samples contain multiple calcite, tin oxide and lead oxide particles. The colour is due to copper, which could only be identified with the application of TEM analysis, in the form of copper oxide nanoparticles. The present study highlights the complicated traditions employed for the production of opaque glass in the post-Medieval European workshops and it underscores the need for a more thorough study of related material.
Symmetry
We investigated the influence of precession angle, energy filtering and sample thickness on the s... more We investigated the influence of precession angle, energy filtering and sample thickness on the structural parameters of amorphous SiO2 thin films from the electron reduced density functions obtained by applying precession electron diffraction. The results demonstrate that the peak positions in the electron reduced density functions are generally insensitive to the studied experimental conditions, while both precession angle and energy filtering influence peak heights considerably. It is also shown that introducing precession with small angles of up to 2 degrees and energy filtering results in higher coordination numbers that are closer to the expected theoretical values of 4 and 2 for Si and O, respectively, for data obtained from a thicker sample.
Microscopy and Microanalysis, 2013
Extended abstract of a paper presented at Microscopy and Microanalysis 2013 in Indianapolis, Indi... more Extended abstract of a paper presented at Microscopy and Microanalysis 2013 in Indianapolis, Indiana, USA, August 4 – August 8, 2013.
Acta Crystallographica Section A Foundations of Crystallography, 2012
Spatial resolution limitation of orientation imaging v1a conventional electron backscattered diff... more Spatial resolution limitation of orientation imaging v1a conventional electron backscattered diffraction (EBSD) analysis in SEM microscopes hinders the investigation of microstructural features whose dimensions are in the range 1 - 5 nm. The use of the recently developed transmission electron microscope (TEM) based technique coupled with electron beam precession, known as AST AR, offers the possibility to acquire reliable orientation/phase maps with a spatial resolution down to 1 nm. The technique, which can be used with nearly all TEM, consists in scanning the electron beam, in nano-probe mode, over the specimen area while precession electron diffraction (PED) spot patterns are collected and indexed automatically through template matching. Several examples of applications of this tool in investigating microstructure I micro-texture of nano-crystalline materials (metals, ceramics, minerals) are presented.
Journal of Solid State Chemistry, 1990
The room temperature single-crystal X-ray data of Na1.5(H3O)0.5 Fe10ZnO17 + 0.3H2O (hydrated sodi... more The room temperature single-crystal X-ray data of Na1.5(H3O)0.5 Fe10ZnO17 + 0.3H2O (hydrated sodium beta'' alumina-like ferrite) were refined. The space group is R3m and the hexagonal cell parameters are a = 5.940, c = 35.731 Å. Water molecules are localized in the conduction region and the total amount of absorbed water depends on hydration conditions, leading to different possible chemical compositions. By thermogravimetric methods the amount of the absorbed water could be measured. This compound is a poor ionic conductor (sigma25°C = 1.27 × 10-10 Omega-1 cm-1) in comparison with beta'' aluminas. Two distinct types of magnetic behavior were observed for crystals of the same preparation, but in all cases water uptake leads to an enhancement of a ferromagnetic component. Dilatometric measurements performed on single crystals revealed the influence of water desorption on cell parameters.
A new automated crystal orientation and phase mapping tool is described. This transmission electr... more A new automated crystal orientation and phase mapping tool is described. This transmission electron microscope accessory combines a diffraction pattern acquisition system involving a CCD camera with pattern identification software that makes use of fast template-matching algorithms. The quality and reliability of pattern identification is substantially improved by combining the system to an electron beam precession device. Examples of phase and orientations maps constructed in only a few minutes are detailed.
Proceedings, annual meeting, Electron Microscopy Society of America, 1990
BaFe2O4 appears at the initial stage of the solid state reaction during the synthesis of hexaferr... more BaFe2O4 appears at the initial stage of the solid state reaction during the synthesis of hexaferrites with Ba as divalent cation. In the HREM study of this phase, linear defects like crystallographic shear planes are observed which could change the ideal stoichiometry. Crystals are twinned, confirming previously predicted results from X-Ray data.Although the crystal structure and superstructure of the BaFe2O4 is well established, the microstructure still remains unknown. This phase is always present during the synthesis of several hexaferrites; the study of the microstructure could help to the understanding of the solid state reaction to synthetize new ferrite phases.A series with nominal composition Ba2Cu2Fe12022 (Y type hexagonal ferrite) was prepared with different annealing conditions for each sample. Details about the thermal treatments and the final products are given elsewhere. From X-Ray powder diffraction data, the presence of BaFe204 is always identificated at the final pr...
Http Www Theses Fr, 1989
SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc
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Papers by STAVROS NICOLOPOULOS