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. 2021 Oct 30;8(Pt 6):860-866.
doi: 10.1107/S2052252521010101. eCollection 2021 Nov 1.

Revealing the early stages of carbamazepine crystallization by cryoTEM and 3D electron diffraction

Edward T Broadhurst  1 , Hongyi Xu  2 , Simon Parsons  1 , Fabio Nudelman  1
Affiliations

Revealing the early stages of carbamazepine crystallization by cryoTEM and 3D electron diffraction

Edward T Broadhurst et al. IUCrJ. .

Abstract

Time-resolved carbamazepine crystallization from wet ethanol has been monitored using a combination of cryoTEM and 3D electron diffraction. Carbamazepine is shown to crystallize exclusively as a dihydrate after 180 s. When the timescale was reduced to 30 s, three further polymorphs could be identified. At 20 s, the development of early stage carbamazepine dihydrate was observed through phase separation. This work reveals two possible crystallization pathways present in this active pharmaceutical ingredient.

Keywords: 3D electron diffraction; carbamazepine; cryoTEM; crystal nucleation; polymorphism.

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Figures

Figure 1
Figure 1
(a) Low-magnification image of CBZDH crystallized after 3 min on the TEM grid at 100 K showing an elongated morphology. Scale bar = 5 µm. (b) Selected crystal of CBZDH used for collection of 3D ED data. Scale bar = 2 µm. Inset shows a diffraction image from the dataset. (c) Disordered structure of CBZDH.
Figure 2
Figure 2
(a)–(c) Crystals of form III, IV and II, respectively, found in a sample after crystallization for 30 s on a TEM grid. Scale bars = 2 µm. The insets show representative frames from the data collections. (d)–(f) Corresponding 3D ED reciprocal lattice reconstructions all viewed along b*. All images were measured at 100 K.
Figure 3
Figure 3
Images taken at 100 K after crystallization for 20 s and vitrification. Scale bar = 2 µm. I shows the droplet-like structures with a surrounding film of mother liquor and II shows the same structures without the surrounding film. III and IV show these structures coalescing inside and outside the film.
Figure 4
Figure 4
Images taken at room temperature after crystallization for 20 s and no vitrification. (a) Droplet-like features with roughened edges after removal of their surrounding mother liquor by the vacuum in the TEM. (b) Coalescence of the droplet structures producing two crystals of CBZDH, identified from morphology. White boxes labelled I, II and III show magnified areas within the sample. Scale bars = 2 µm.
See this image and copyright information in PMC

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