A 47-year-old misunderstanding: Indomethacin Polymorph δ revealed to be two plastically bendable crystal forms by 3D electron diffraction

Lightowler, Molly; Li, Shuting; Xiao, Ou; Zou, Xiaodong; Lü, Ming; Xu, Hongyi

doi:10.33774/chemrxiv-2021-s9fhf

Cited by 3 publications

(3 citation statements)

References 53 publications

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“…Finally, although more in-depth stability analyses are needed, the results obtained from the present dissolution studies suggest that δ-indomethacin is very soluble compared with other polymorphs and therefore appears particularly suitable for use in immediate-release formulations. Whilst this paper was under review, a second independent structure determination of δ-IMC by 3D ED was reported in a preprint draft focused on polymorphic plasticity and melt crystallization (Lightowler et al, 2021). The availability of 3D electron diffraction, a new and efficient method for structure characterization of poorly crystalline polymorphic forms, appears therefore more and more important for assessing the energy landscape of API's, predicting their real potential for medicinal applications and possibly designing more efficient administration strategies.…”

Section: Discussionmentioning

confidence: 99%

Structure determination, thermal stability and dissolution rate of δ-indomethacin

Andrusenko

Hamilton

Lanza

et al. 2021

International Journal of Pharmaceutics

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Section: Discussionmentioning

confidence: 99%

Structure determination, thermal stability and dissolution rate of δ-indomethacin

Andrusenko

Hamilton

Lanza

et al. 2021

International Journal of Pharmaceutics

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“…These techniques have proven successful for structure characterization of many polycrystalline materials that are typically out-of-reach for X-ray diffraction methods owing to small crystal sizes, radiation sensitivity or the presence of multiple phases. These include zeolites (Jiang et al, 2011;Willhammar et al, 2014;Guo et al, 2015;Luo et al, 2023), metal-organic frameworks and covalent organic frameworks (Feyand et al, 2012;Zhang et al, 2013;Wang et al, 2018;Huang et al, 2021), proteins and polypeptides (Shi et al, 2013;Sawaya et al, 2016;Xu et al, 2019;Clabbers et al, 2021), pharmaceuticals (Bra ´zda et al, 2019;Gruene et al, 2018;Jones et al, 2018;Clabbers & Xu, 2020;Lightowler et al, 2022), and so forth .…”

Section: Introductionmentioning

confidence: 99%

STEM SerialED: achieving high-resolution data for ab initio structure determination of beam-sensitive nanocrystalline materials

Hogan-Lamarre,

Luo,

Bücker

et al. 2024

IUCrJ

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Serial electron diffraction (SerialED), which applies a snapshot data acquisition strategy for each crystal, was introduced to tackle the problem of radiation damage in the structure determination of beam-sensitive materials by three-dimensional electron diffraction (3DED). The snapshot data acquisition in SerialED can be realized using both transmission and scanning transmission electron microscopes (TEM/STEM). However, the current SerialED workflow based on STEM setups requires special external devices and software, which limits broader adoption. Here, we present a simplified experimental implementation of STEM-based SerialED on Thermo Fisher Scientific STEMs using common proprietary software interfaced through Python scripts to automate data collection. Specifically, we utilize TEM Imaging and Analysis (TIA) scripting and TEM scripting to access the STEM functionalities of the microscope, and DigitalMicrograph scripting to control the camera for snapshot data acquisition. Data analysis adapts the existing workflow using the software CrystFEL, which was developed for serial X-ray crystallography. Our workflow for STEM SerialED can be used on any Gatan or Thermo Fisher Scientific camera. We apply this workflow to collect high-resolution STEM SerialED data from two aluminosilicate zeolites, zeolite Y and ZSM-25. We demonstrate, for the first time, ab initio structure determination through direct methods using STEM SerialED data. Zeolite Y is relatively stable under the electron beam, and STEM SerialED data extend to 0.60 Å. We show that the structural model obtained using STEM SerialED data merged from 358 crystals is nearly identical to that using continuous rotation electron diffraction data from one crystal. This demonstrates that accurate structures can be obtained from STEM SerialED. Zeolite ZSM-25 is very beam-sensitive and has a complex structure. We show that STEM SerialED greatly improves the data resolution of ZSM-25, compared with serial rotation electron diffraction (SerialRED), from 1.50 to 0.90 Å. This allows, for the first time, the use of standard phasing methods, such as direct methods, for the ab initio structure determination of ZSM-25.

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“…In many cases, nano-crystalline materials do not provide sufficiently high resolution diffraction data, whether due to poor crystallinity or radiation damage during data collection. In these situations, direct-space global optimization methods, typically simulated annealing (SA), are employed (Andrusenko et al, 2021;Lightowler et al, 2022). SA requires a complete molecule, the position and orientation of which within the unit cell are varied in accordance with the symmetry, until an acceptable agreement between the experimental and calculated diffraction data is reached.…”

Section: Introductionmentioning

confidence: 99%

Molecular replacement for small-molecule crystal structure determination from X-ray and electron diffraction data with reduced resolution

Gorelik,

Lukat,

Kleeberg

et al. 2023

Acta Crystallogr A Found Adv

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The resolution of 3D electron diffraction (ED) data of small-molecule crystals is often relatively poor, due to either electron-beam radiation damage during data collection or poor crystallinity of the material. Direct methods, used as standard for crystal structure determination, are not applicable when the data resolution falls below the commonly accepted limit of 1.2 Å. Therefore an evaluation was carried out of the performance of molecular replacement (MR) procedures, regularly used for protein structure determination, for structure analysis of small-molecule crystal structures from 3D ED data. In the course of this study, two crystal structures of Bi-3812, a highly potent inhibitor of the oncogenic transcription factor BCL6, were determined: the structure of α-Bi-3812 was determined from single-crystal X-ray data, the structure of β-Bi-3812 from 3D ED data, using direct methods in both cases. These data were subsequently used for MR with different data types, varying the data resolution limit (1, 1.5 and 2 Å) and by using search models consisting of connected or disconnected fragments of BI-3812. MR was successful with 3D ED data at 2 Å resolution using a search model that represented 74% of the complete molecule.

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A 47-year-old misunderstanding: Indomethacin Polymorph δ revealed to be two plastically bendable crystal forms by 3D electron diffraction

Cited by 3 publications

References 53 publications

Structure determination, thermal stability and dissolution rate of δ-indomethacin

Structure determination, thermal stability and dissolution rate of δ-indomethacin

STEM SerialED: achieving high-resolution data for ab initio structure determination of beam-sensitive nanocrystalline materials

Molecular replacement for small-molecule crystal structure determination from X-ray and electron diffraction data with reduced resolution

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