What advantages does 3D ED/MicroED provide over conventional single-crystal X-ray diffraction?

The primary advantage is the ability to determine crystal structures from crystals smaller than 1 μm, which are often too small for conventional X-ray diffraction. Because electrons interact much more strongly with matter than X-rays, high-quality diffraction data can be collected from nanometer-scale crystals. Modern detectors also minimize beam damage, allowing sensitive organic and biological materials to be analyzed efficiently.

Why is direct analysis of pharmaceutical tablets valuable for structural characterization?

Many active pharmaceutical ingredients exist as microcrystals within finished tablets, making them difficult to analyze by traditional single-crystal X-ray methods. Electron diffraction allows these crystals to be examined directly after simple sample preparation, avoiding recrystallization that could alter the crystal form. This preserves the original solid-state structure while reducing analysis time and simplifying pharmaceutical development workflows.

How can 3D ED/MicroED be used to study crystal polymorphism?

The technique can rapidly collect diffraction data from hundreds of individual microcrystals using automated acquisition. Each crystal can be identified and structurally characterized, allowing researchers to determine both the proportion of different polymorphs and their individual crystal structures. This provides quantitative phase information together with detailed crystallographic data in a single workflow.

Can electron diffraction determine the absolute configuration of chiral molecules?

Yes. Instead of relying on anomalous scattering as in X-ray diffraction, electron diffraction exploits multiple scattering effects during dynamical refinement. By comparing refinement statistics for alternative enantiomeric models, the correct absolute structure can be identified, including for compounds composed primarily of light elements where X-ray methods may require much more extensive data collection.

What role does automation play in modern electron diffraction workflows?

Automation simplifies data collection, processing, and structure determination by integrating these steps into a single software environment. Multiple crystals can be measured sequentially, while data reduction and structure solution proceed automatically. This increases throughput, reduces operator intervention, and makes electron diffraction accessible to researchers without extensive electron microscopy experience.

Are X-ray crystallography and 3D ED/MicroED competing or complementary techniques?

They are complementary methods. X-ray crystallography remains the preferred approach for many larger, well-diffracting crystals, while 3D ED/MicroED excels when only nanometer-scale crystals are available or when conventional X-ray diffraction struggles to obtain sufficient data. Using both techniques together allows researchers to choose the most effective approach for each sample and to validate structural results when appropriate.

Which research fields benefit most from 3D ED/MicroED?

The technique is valuable across pharmaceutical development, organic chemistry, materials science, and structural biology. It is particularly useful whenever only submicron crystals are available, when rapid polymorph identification is needed, or when determining the structure of compounds that cannot easily be recrystallized into crystals suitable for conventional X-ray diffraction.

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Structure Analysis of Nano-size Crystals by the XtaLAB Synergy-ED: An Integrated Platform for 3D ED/MicroED

Sho Ito and Akihito Yamano

Winter 2023 Volume 39, No. 1 , 06-09

3D ED/microED has been attracting much attention because it enables structure analysis of crystals smaller than 1 μm. In this article, examples of crystal structure analysis and some applications of MicroED/3D ED will be presented.

Despite increasing demand for 3D ED/MicroED, measurement and analysis with this analytical technique has not been straightforward. Until recently, electron diffraction experiments were performed mainly as a function of general-purpose transmission electron microscopes. The hurdles were higher than those for X-ray structural analysis because it required an expert in electron microscopy to determine the optimal setting of the equipment for diffraction experiments. To address this situation, Rigaku and JEOL jointly developed an electron diffraction platform dedicated to 3D ED/ MicroED. The system is called XtaLAB Synergy-ED. With the Synergy-ED, anyone can easily perform electron diffraction experiments.

Highlights

3D ED/MicroED enables routine crystal structure determination of submicron crystals that are too small for conventional single-crystal X-ray diffraction.
Dedicated electron diffraction platforms can rapidly determine structures directly from real-world samples, including pharmaceutical tablets, without recrystallization.
Automated workflows support polymorph identification, quantitative phase analysis, and absolute structure determination, making electron diffraction a powerful complement to X-ray crystallography.

Summary

Three-dimensional electron diffraction (3D ED/MicroED) has become an important structural analysis technique for crystals smaller than approximately 1 μm, extending crystallographic studies to samples that are difficult or impossible to analyze with conventional X-ray diffraction. Because electrons interact with matter much more strongly than X-rays, extremely small crystals can produce measurable diffraction patterns while advances in detector technology have significantly reduced beam damage, enabling routine analysis of sensitive organic and biological materials.

A dedicated electron diffraction platform integrates data collection, processing, and structure solution into a streamlined workflow that reduces the expertise traditionally required for electron diffraction experiments. The system demonstrates that electron diffraction is not only valuable for nanocrystals but can also outperform X-ray diffraction for certain poorly diffracting samples by producing higher-quality structural data.

Pharmaceutical analysis is one of the most compelling applications. Microcrystals embedded within tablets can be analyzed directly after simple sample preparation, eliminating the need for recrystallization and preserving the crystal form present in the finished product. This approach enables rapid identification of active pharmaceutical ingredients, excipients, and other crystalline phases while significantly accelerating structural characterization during drug development.

The technique also enables automated quantitative analysis of crystalline polymorphs by measuring large numbers of individual microcrystals in sequence. Beyond determining the relative abundance of each polymorph, it simultaneously provides complete structural information for each crystal, offering insights that are difficult to obtain from bulk diffraction methods alone.

Another important capability is the determination of absolute structure using dynamical refinement based on multiple scattering effects. Unlike conventional X-ray methods that rely on anomalous dispersion, this approach can accurately determine the handedness of compounds composed primarily of light elements, often with dramatically shorter measurement times. Rather than replacing X-ray crystallography, 3D ED/MicroED serves as a complementary technique, allowing researchers to select the most appropriate method based on crystal size, sample availability, and analytical objectives.

Frequently asked questions

: The primary advantage is the ability to determine crystal structures from crystals smaller than 1 μm, which are often too small for conventional X-ray diffraction. Because electrons interact much more strongly with matter than X-rays, high-quality diffraction data can be collected from nanometer-scale crystals. Modern detectors also minimize beam damage, allowing sensitive organic and biological materials to be analyzed efficiently.
: Many active pharmaceutical ingredients exist as microcrystals within finished tablets, making them difficult to analyze by traditional single-crystal X-ray methods. Electron diffraction allows these crystals to be examined directly after simple sample preparation, avoiding recrystallization that could alter the crystal form. This preserves the original solid-state structure while reducing analysis time and simplifying pharmaceutical development workflows.
: The technique can rapidly collect diffraction data from hundreds of individual microcrystals using automated acquisition. Each crystal can be identified and structurally characterized, allowing researchers to determine both the proportion of different polymorphs and their individual crystal structures. This provides quantitative phase information together with detailed crystallographic data in a single workflow.
: Yes. Instead of relying on anomalous scattering as in X-ray diffraction, electron diffraction exploits multiple scattering effects during dynamical refinement. By comparing refinement statistics for alternative enantiomeric models, the correct absolute structure can be identified, including for compounds composed primarily of light elements where X-ray methods may require much more extensive data collection.
: Automation simplifies data collection, processing, and structure determination by integrating these steps into a single software environment. Multiple crystals can be measured sequentially, while data reduction and structure solution proceed automatically. This increases throughput, reduces operator intervention, and makes electron diffraction accessible to researchers without extensive electron microscopy experience.
: They are complementary methods. X-ray crystallography remains the preferred approach for many larger, well-diffracting crystals, while 3D ED/MicroED excels when only nanometer-scale crystals are available or when conventional X-ray diffraction struggles to obtain sufficient data. Using both techniques together allows researchers to choose the most effective approach for each sample and to validate structural results when appropriate.
: The technique is valuable across pharmaceutical development, organic chemistry, materials science, and structural biology. It is particularly useful whenever only submicron crystals are available, when rapid polymorph identification is needed, or when determining the structure of compounds that cannot easily be recrystallized into crystals suitable for conventional X-ray diffraction.

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Structure Analysis of Nano-size Crystals by the XtaLAB Synergy-ED: An Integrated Platform for 3D ED/MicroED

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