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. 2016 Mar;72(Pt 2):236-42.
doi: 10.1107/S2053273315022500. Epub 2016 Feb 5.

Ab initio structure determination of nanocrystals of organic pharmaceutical compounds by electron diffraction at room temperature using a Timepix quantum area direct electron detector

E van Genderen  1 , M T B Clabbers  1 , P P Das  2 , A Stewart  3 , I Nederlof  1 , K C Barentsen  1 , Q Portillo  2 , N S Pannu  1 , S Nicolopoulos  2 , T Gruene  4 , J P Abrahams  1
Affiliations

Ab initio structure determination of nanocrystals of organic pharmaceutical compounds by electron diffraction at room temperature using a Timepix quantum area direct electron detector

E van Genderen et al. Acta Crystallogr A Found Adv. 2016 Mar.

Erratum in

Abstract

Until recently, structure determination by transmission electron microscopy of beam-sensitive three-dimensional nanocrystals required electron diffraction tomography data collection at liquid-nitrogen temperature, in order to reduce radiation damage. Here it is shown that the novel Timepix detector combines a high dynamic range with a very high signal-to-noise ratio and single-electron sensitivity, enabling ab initio phasing of beam-sensitive organic compounds. Low-dose electron diffraction data (∼ 0.013 e(-) Å(-2) s(-1)) were collected at room temperature with the rotation method. It was ascertained that the data were of sufficient quality for structure solution using direct methods using software developed for X-ray crystallography (XDS, SHELX) and for electron crystallography (ADT3D/PETS, SIR2014).

Keywords: Timepix quantum area detector; carbamazepine; electron diffraction structure determination; electron nanocrystallography; nicotinic acid.

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Figures

Figure 1
Figure 1
(a) Detector mounted at the on-axis camera position on a CM30 (University of Barcelona, CciTUB services, Spain). (b) 90° cut-off schematic of the camera as designed for the CM200 (Technische Universiteit Delft, The Netherlands).
Figure 2
Figure 2
(a) Linear cross section through an image recorded with the Timepix detector ranges from 0 counts (marked red, set to 100 for visibility) to 10 020. Note the absence of a beamstop! (b) Spot separation of closely neighbouring spots in the absence of ‘blooming’ effects.
Figure 3
Figure 3
Rotation electron diffraction of pharmaceutical nanocrystals showing in the left panel an image of the crystal at 5.3k times magnification and in the right panel a diffraction pattern: (a) a 200 nm-thin carbamazepine crystal, (b) a 200 nm-thin nicotinic acid crystal.
Figure 4
Figure 4
Unit-cell content for the final refined structures of carbamazepine (a) and nicotinic acid (b) for the single-crystal data set, Table 1 ▸. Insets show the SHELXT solutions.
See this image and copyright information in PMC

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