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

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.

SUBMITTER: Broadhurst ET

PROVIDER: S-EPMC8562671 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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

Broadhurst Edward T ET Xu Hongyi H Parsons Simon S Nudelman Fabio F

IUCrJ 20211030 Pt 6

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 ...[more]

PMID: 34804540

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Project description:Crystal and conformational polymorphisms play crucial roles in the physical and chemical properties of materials, impacting their stability, solubility, and bioavailability, which are essential for various applications in pharmaceuticals, materials science, and chemistry. Despite their significance, the structural analysis of these polymorphisms, particularly conformational polymorphisms, remains challenging due to the limited methodology that provides sufficient resolution for microcrystalline variants of polymorphs. Three-dimensional electron diffraction (3D ED) is an emerging technique with significant potential for elucidating the microcrystal structures of functional organic molecules, pharmaceuticals, and biomolecules. Despite this potential, there are limited instances of 3D ED structures for small molecules exhibiting the lowest crystallographic symmetry with a preferred orientation and possibly conformational variations of constituent molecules. A novel organic semiconductor, Ph-anti-benzothieno[5,6-b]benzothieno[3,2-b]thiophene-C10 (antiC10), is one of such examples. We successfully determined the 3D ED structure of this challenging molecule. The antiC10 crystal exhibited the lowest symmetry (space group P1), and the preferred orientations against the grid resulted in a missing cone. These challenges were surmounted by employing a sequential molecular replacement approach with an ab initio-generated search model. The resulting octameric antiC10 structure reveals a two-monolayer architecture and an antiparallel alkyl-interdigitated herringbone configuration in contrast to the all-parallel associations observed in its previously reported isomer. Concurrently, the alkyl chains are intricately interdigitated with each other and positioned between the adjacent π-core strata. Detailed analysis has elucidated the conformational polymorphism in herringbone packing between the two monolayers as well as in intramolecular conformations among monomers. The structure with conformational polymorphism is presumably in a metastable intermediate state, stabilized by twinning. These findings may provide critical insights into the crystallization mechanisms and rational design of organic semiconductors. This research demonstrates that advancements in 3D ED technology and sequential phasing methodologies have enabled the study of previously unreachable structures.

Dataset Information

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

Publications

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

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