Papers by Stavros Nicolopoulos
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.
Microscopy and Microanalysis, Jul 22, 2023
Acta Crystallographica, Aug 23, 2015
A recently developed automated technique for the mapping of crystal phases and orientations of po... more A recently developed automated technique for the mapping of crystal phases and orientations of polycrystalline materials in a transmission electron microscope has been applied to a mixture of ironoxide nano-crystals.
Microscopy and Microanalysis, Aug 1, 2013
Meeting abstracts, 2014
Transformations in Li-rich layered oxides have been extensively studied recently for their potent... more Transformations in Li-rich layered oxides have been extensively studied recently for their potential application in Li-ion batteries. These materials have attracted a lot of interest due to the high capacity offered by them. However, the structure of these materials in their pristine state is not clearly understood. Several reports have assigned their structure to be trigonal (R-3m), monoclinic (c2/m), or a combination of both (composite). The present study discusses the structure of Li1.2(Ni0.13Mn0.54Co0.13) O2 prepared with two different morphologies: plates and needles, using the results obtained from aberration corrected (scanning) transmission electron microscopy, electron energy loss spectroscopy (EELS), convergent beam electron diffraction and precession electron diffraction tomography and question the validity of the the claims of them being “composite”. It was found that these materials consist of domains which correspond to variants of monoclinic structure. It will be shown how diffraction-based experiments on such materials can often lead to misleading conclusions, since analysis of diffraction-based techniques inevitably assign them as trigonal, although the present study shows that the three-fold symmetry observed in electron diffraction patterns result from the combination of the variants having monoclinic structure. Furthermore, results from STEM and EELS experiments showed that the pristine materials have several defects consisting of differently ordered structure on their surface, and several Cobalt-rich line defects. These results prescribe that extreme care should be taken while interpreting the electron microscopy results obtained from cycled samples.
Microscopy and Microanalysis, Jul 1, 2011
ChemInform, Aug 4, 2010
A New Microporous Polymorph of Silica Isomorphous to Zeolite MCM-22.-A novel polymorph of silica,... more A New Microporous Polymorph of Silica Isomorphous to Zeolite MCM-22.-A novel polymorph of silica, ITQ-1, which is isomorphous to zeolite MCM-22, is prepared hydrothermally from SiO2 in the presence of a mixture of hexamethyleneimine and N,N,N-trimethyl-1-adamantammonium hydroxide in 1.2 molar ratio as organic additives. By calcination at 580 • C the occluded organics are removed and the XRD pattern of the calcined ITQ-1 corresponds to that of calcined MCM-22. A low concentration of connectivity defects (≈7 mol% Si(OSi)3OH compared to 30 mol% in uncalcined ITQ-1) are shown to arise mainly from unconnected T1-O-T1 and T2-O-T3 bonds where T1,T2,T3 represent the tetrahedral sites 1 to 3 of the hexagonal unit cell.
Acta Crystallographica Section A, Aug 6, 2006
ChemInform, Jun 23, 2010
Incorporation of Buckminsterfullerene C 60 in the Supercages of Zeolite Y.-A series of vapor-phas... more Incorporation of Buckminsterfullerene C 60 in the Supercages of Zeolite Y.-A series of vapor-phase adsorptions of C 60-fullerene on the Na +-form of Y faujasite, a tridirectional large-pore zeolite, at high temperature and reduced pressure are carried out. High-resolution electron microscopy provides experimental evidence that only a very small fraction of C 60 has penetrated inside the supercages while most of the fullerene molecules are located in the open cavities at the external surface. These experimental observations completely agree with theoretical predictions.
Acta Crystallographica, Aug 5, 2014
Since the invention of Precession Electron Diffraction (PED) in Transmission Electron Microscopy ... more Since the invention of Precession Electron Diffraction (PED) in Transmission Electron Microscopy (TEM) by Vincent & Midgley [1] in 1994 and mainly after the introduction of dedicated PED devices to different TEM, the structure of various nano-sized crystals have been solved by Electron Crystalography. The most popular technique that was recently developed based on beam precession is the 3D Precession Diffraction Tomography (PEDT) [2]. A series of ED patterns are collected every 1° while the sample is tilted around the goniometer axis. By the automatic measurement of ED intensities (ADT 3D software), the unit cell, crystal symmetry and the detailed crystal structure can be determined. A large number of crystal structures, such as complex metals, alloys, organic pigments, MOF, catalysts etc., have been solved by the 3D PEDT technique. A drawback of 3D PEDT (especially for beam sensitive materials) is the long acquisition times (45-120 min), due to the time consuming step of tracking the crystal under the beam during tilting. To deal with this problem, we have developed two novel approaches: the Random Electron Diffraction Tomography (rPEDT) technique and the Ultra-Fast 3D diffraction tomography (UF PEDT) [3]. By rPEDT technique, a sample area (few microns), where several crystals in different (random) orientations are present, is scanned rapidly using an ASTAR precession device (NanoMEGAS SPRL). PED patterns of all scanned crystals are collected by a fast speed CCD camera (up to 120 frames/sec; 8/12 bit). Concerning UF PEDT, the data acquisition time can be 10-20 times faster compared to hitherto 3D PEDT procedure. UF PEDT can be applied when the crystal shift is stable and reproducible during tilting the sample for a specific tilt range. Thus, such crystals can be tracked by shifting the beam following the crystal displacement during tilting (using ASTAR beam scanning). Obtained PED patterns can be recorded with a fast CCD camera, while crystal is tilted. As a conclusion, rPEDT and UF-PEDT can be considered as breakthrough techniques in electron crystallography as they can be performed in any commercial TEM. Both techniques reduce considerable 3D intensity data acquisition time, and allow the analysis of unknown compounds, including beam sensitive organic crystals, as fast techniques prevents crystal beam damage. The authors acknowledge financial support from EU ESTEEM-2 project (European Network for Electron Microscopy www.esteem2.eu).
Microscopy and Microanalysis, Feb 28, 2014
Acta Crystallographica Section A, Aug 7, 2012
Microscopy and Microanalysis, Jul 1, 2011
Electron backscatter diffraction (EBSD) technique in a scanning electron microscope (SEM) is ofte... more Electron backscatter diffraction (EBSD) technique in a scanning electron microscope (SEM) is often employed for the structural characterization of thin polycrystalline films and texture acquisition of surfaces for metals and minerals. However, the EBSD-SEM technique has limited spatial resolution (>30 nm for SEM with a Field Emission Gun) and is very sensitive to sample preparation-induced surface roughness and damage.
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Papers by Stavros Nicolopoulos