From Powders to Single Crystals: A Crystallographer's Toolbox for Small-Molecule Structure Determination

Area of Science:

• Crystallography and Materials Science
• Chemical Structure Elucidation

Background:

• Single-crystal X-ray diffraction (scXRD) is the standard for small-molecule crystal structure determination.
• Emerging techniques like three-dimensional electron diffraction (3DED) and computational crystal structure prediction (CSP) offer potential advancements.
• These methods expand the available toolkit for crystallographers.

Purpose of the Study:

• To comparatively assess the capabilities of scXRD, 3DED, and CSP.
• To evaluate these methods in conjunction with powder X-ray diffraction (PXRD).
• To apply the assessment to former drug candidate compounds and a multicomponent crystal relevant to gefapixant citrate synthesis.

Main Methods:

• Single-crystal X-ray diffraction (scXRD)
• Three-dimensional electron diffraction (3DED)
• Crystal structure prediction (CSP) combined with powder X-ray diffraction (PXRD)

Main Results:

• Comparative analysis of scXRD, 3DED, and CSP on selected compounds.
• Demonstration of the utility of 3DED and CSP as complementary structure elucidation tools.
• Successful application to complex systems including multicomponent crystals.

Conclusions:

• 3DED and CSP, alongside scXRD and PXRD, provide a robust and expanded framework for crystal structure determination.
• These integrated approaches enhance the ability to elucidate structures of small molecules and complex crystalline materials.
• The findings support the broader adoption of these advanced techniques in chemical research and development.