Scientific principle and analytical basis
MicroED is electron diffraction applied to very small crystals. It can provide crystallographic structure information when suitable single crystals cannot be grown for SCXRD.
Start with the decision and the sample
MicroED uses electron diffraction from nanocrystals or microcrystals to support structure determination, form confirmation, impurity identification, and salt/cocrystal classification.
This decision-focused guide explains the scientific measurement basis, when to use it, its limitations, sample amount considerations, competing methods, FDA-facing concerns, and common mistakes.
Overview of Micro Crystal Electron Diffraction Services
When is it used?
Use MicroED for microcrystalline APIs, impurities, salts, cocrystals, polymorphs, and particles where molecular structure or ionization state is needed but SCXRD crystals are unavailable.
What are limitations?
MicroED still requires crystalline material, careful sample preparation, and crystallographic interpretation. Beam sensitivity, preferred orientation, mixtures, and sample heterogeneity can limit certainty.
What sample amounts are needed?
MicroED can work with very small crystals and small quantities, but enough representative particles must be available for screening, grid preparation, and data collection.
What techniques compete with it?
SCXRD, XRPD, solid-state NMR, Raman/IR, HRMS, chromatography, and computational methods compete or complement MicroED depending on whether the decision is structure, phase ID, purity, or molecular formula.
What does FDA care about?
FDA-facing work should connect the method to a quality attribute, document sample preparation and specificity, and support validation or verification where the result is used for release, stability, or regulatory decisions.
What are common mistakes?
Common mistakes include treating instrument output as interpretation, using a non-representative matrix, failing to document sample handling, or not using orthogonal methods when the first method is not specific enough.
What is Triclinic's experience with this technique
Triclinic uses MicroED when crystals are too small for conventional single-crystal X-ray diffraction but molecular-level structural evidence is still needed. Real-world applications include structure determination for microcrystalline APIs, salts, cocrystals, impurities, degradants, and reference materials, especially when powder diffraction, spectroscopy, or chromatography indicates a distinct phase but does not provide a complete structural answer.
Specific instruments and capabilities for Micro Crystal Electron Diffraction Services
The table below lists the specific platforms, brands, models, software, detectors, and capability notes relevant to this service area.
| Instrument or platform | Brand, model, software, or detector | Additional capabilities and use |
|---|---|---|
| MicroED diffractometer | ELDICO ED-1 | Electron diffraction structure determination and absolute-configuration support from nanocrystalline material. |
| Continuous-rotation electron diffraction | ELDICO ED-1 fixed-beam, continuous-rotation scanning mode | Reduced beam damage compared with TEM-magnet approaches; efficient collection for beam-sensitive molecular crystals. |
| Automated processing suite | ED-1 automated data-processing software suite | Unit-cell generation, crystallographic refinement, dynamical processing/refinement, and structural configuration workflows. |
| Sample scale and crystal-size capability | MicroED workflow for 10-1000 nm crystallites and <1 mg solid-material projects | Structure determination when bulk single-crystal growth fails; impurity particle, phase-ID, supplier-verification, and process-chemistry support. |
| Orthogonal impurity workflow | MicroED integrated with HRMS and LC fraction-isolation workflows | High-confidence impurity structure determination by combining accurate mass, molecular formula constraints, and crystallographic structure solution. |
MicroED Structure Determination from Microcrystals Example
This example reflects the central MicroED use case on the legacy Triclinic page: extracting crystallographic structure information from crystals far smaller than those typically required for single-crystal X-ray diffraction. MicroED is most valuable when molecular structure, salt/cocrystal classification, polymorph confirmation, or impurity structure is needed but the material will not grow suitable larger single crystals.
Technical Resources and Publications
These examples include technical resources, regulatory guidances, or literature relevant to the technique. Download buttons are placed at the bottom-left of each example.
Molecular Structure Solution of Impurities in Liquid Chromatography Assays using MicroED and HRMS
Author: Gary C. George III, Jason Vanlerberghe, and Stephan X.M. Boerrigter
Publication date: Q1 2026
Abstract: This Triclinic white paper explains a hybrid workflow in which HRMS provides accurate-mass/formula constraints and MicroED provides crystallographic structure evidence for trace impurities that may be difficult to isolate in amounts needed for traditional methods.
A Comprehensive Approach for Solid Form Selection in Preclinical Development and Beyond
Author: Melanie Bevill, Chris Seadeek, Nico Setiawan, Shawn Comella, Blaise Mibeck, and Steef Boerrigter
Publication date: November 2023
Abstract: This Triclinic application note links solid-form screening and selection to crystallinity, stability, solubility, hygroscopicity, manufacturability, regulatory needs, and IP objectives. It supports choosing analytical techniques based on the development decision rather than a fixed instrument list.
ICH Q2(R2) Validation of Analytical Procedures and ICH Q14 Analytical Procedure Development
Author: International Council for Harmonisation / FDA
Publication date: 2024
Abstract: FDA notes that ICH Q2(R2) and Q14 describe validation and development principles for analytical procedures used to assess drug substance and drug product quality. These guidances frame FDA expectations for specificity, accuracy, precision, range, robustness, lifecycle management, and fit-for-purpose method evidence.
Competing and complementary techniques
Bulk Powder API & Excipient Characterization
Use this technique when its evidence better matches the sample, matrix, or development decision.
View techniqueDiffraction Analysis
Use this technique when its evidence better matches the sample, matrix, or development decision.
View techniqueThermal Analysis
Use this technique when its evidence better matches the sample, matrix, or development decision.
View techniqueWater Analysis
Use this technique when its evidence better matches the sample, matrix, or development decision.
View techniqueSpectroscopy
Use this technique when its evidence better matches the sample, matrix, or development decision.
View techniqueNMR
Use this technique when its evidence better matches the sample, matrix, or development decision.
View technique
Discuss the right analytical technique
Tell Triclinic what sample you have, what decision the data must support, what prior data are available, and whether cGMP, release, validation, or regulatory documentation is required.
