ORGANICS & PHARMACEUTICALS/PROTEINS

Polymorphism is very important in the pharmaceutical industry where it also occurs very frequently in other organic materials like pigments and proteins. Physical properties of organic compounds (specially for drug design) depend on their precise crystal structure. 3D electron diffraction tomography sheds light to the crystal structure of organic compounds and proteins.

 

Trace analysis with TEM high resolution imaging and electron diffraction

 

From left to right : Virtual Dark Field (VDF) TEM high resolution image showing 10 nm resorcinol crystals (arrows) on amorphous background; corresponding ED patterns for crystallites ; individual Nicotinic acid API nanocrystal and its corresponding ED pattern

High Resolution Virtual Dark Field (VDF) in TEM is a technique that enables detection of very small trace of crystalline material; in the example shown above, trace crystals of very small sizes (eg 10nm) can be observed at very low quantity (< 0.01%). Structure characterization (like phase confirmation) of such small crystals can be done using Electron Diffraction on individual crystallites.

Drug polymorph structure analysis with TEM 3D electron diffraction tomography

 

Electron Crystallography is considered as the method of choice for structure determination of nanocrystalline compounds (crystals as small as 20 nm to several microns). Such nano-crystallites reveal typically “X‐Ray amorphous” powder diffraction patterns (for sizes & 10nm) where is very difficult to identify and characterize their structures using X-Ray diffraction techniques.

Use of precession 3D electron diffraction (PED) with TEM makes possible unit cell and structure determination on individual nanocrystals. Using 3D diffraction tomography, a 3D reconstruction of the reciprocal space can be performed by tilting the sample and recording ED patterns (Fig. 1) (typically ±45° every 1°). Collected electron diffraction (ED) patterns can be processed to precisely determine the unit cell and reveal the space group symmetry of the API crystal. Full atomic crystal structure can also be performed after collection and precise measurement of ED intensities.

From left to right: CM30 (300 KV) Transmission electron microscope (TEM), individual Carbamazepine (CBZ) API crystal, 3D reciprocal space reconstruction of CBZ crystal, CBZ Structure solved from 3D electron diffraction data (50º continuous tilt, 3823 reflections, 0.8º resolution). Cell parameters: a =7.53 Å; b =11.14 Å; c =14.06 Å; β = 92.80 º, P21/n (monoclinic). In blue structure solved by Single crystal X-Ray diffraction, in red structure solved by Electron Diffraction.

WEBINARS

Structural Characterization in TEM by 3D Electron Diffraction / Micro-ED

Dr. Partha Das Application Scientist NanoMEGAS Belgium

 

In recent  years  there has been a huge interest in characterization for various materials where more than 300 structures have been solved (minerals, zeolites, MOFS, aperiodic crystals, archaeological  artefacts, functional materials, organic pharmaceuticals, proteins etc.) using 3D Electron Diffraction from nanometer size crystals in TEM. The principle of acquiring TEM 3D-ED data consists of focusing the electron beam on a nanometer size crystal (50-500 nm), while sampling thereciprocal/diffraction space in small steps using beam precession or continuous  crystal rotation (with or without beam PED,  technique known as 3D Electron Diffraction Tomography/Micro-ED). ED intensities can be registered using CCD cameras or ultra- sensitive pixelated detectors. Acquired 3D-ED data can be used to determine ab-initio  crystal unit cell, space group and atomic positions. Further dynamical refinement can also be performed using PED to detect H atoms, refine occupancies  an  improve  reliability of the structural model down to 1-3 pm accuracy.  In this webinar various examples will be shown how 3D-ED method has been applied successfully to solve structures of a big variety  of  nanocrystalline materials.

PUBLICATIONS

3D ELECTRON DIFFRACTION TOMOGRAPHY – ORGANICS-PHARMACEUTICALS

Schmidt, M. U., et al. “Electron Diffraction, X-Ray Powder Diffraction and Pair-Distribution- Function Analyses to Determine the Crystal Structures of Pigment Yellow 213, C23H21N5O9.” Acta Crystallographica Section B: Structural Science, vol. 65, no. 2, 2009, pp. 189–99, doi:10.1107/S0108768109003759.

3D ELECTRON DIFFRACTION TOMOGRAPHY – PROTEINS

Lanza, A., et al. “Nanobeam Precession-Assisted 3D Electron Diffraction Reveals a New Polymorph of Hen Egg-White Lysozyme.” IUCrJ, vol. 6, International Union of Crystallography, 2019, pp. 178–88, doi:10.1107/S2052252518017657.

APPLICATION NOTES

Structure of pigment yellow for car industry

Structure of organic (CNBA) molecules

Crystal orientation imaging of organic nanomagnets

Revealing Crystal Structure of Carbamazepine with 3D electron diffraction tomography

Revealing Crystal Structure of Nicotinic Acid with 3D electron diffraction tomography

Revealing Crystal Structure of Phenothiazine with 3D electron diffraction tomography

 3D Electron Diffraction / Micro-ED for Structural Characterization of beam sensitive API using Pixelated detectors

Searching for Api Polymorphs and solving their nanocrystal structures by Electro Diffraction Tomography

New Timepix Detector Enables Single Crystal Structure determination from Beams Sensitive Organic Materials using Electron Diffraction

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