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When an impurity is just a peak… can you still solve its structure?

Anyone working in chemical development or production knows the problem: an unexpected HPLC peak appears.
What is it?

And then begins the investigation: isolation, MS, NMR, more isolation, more analyses… sometimes with only tiny amounts of material available.

Electron Diffraction can open a different route to impurity structure determination.

There are two particularly interesting situations.

1 — You can isolate the impurity, but you only have a few milligrams

The impurity is detected by HPLC and isolated by preparative or semi-preparative chromatography.
At this stage, the amount available may be extremely small — sometimes only a few milligrams — and the isolated material may even be an oil.
Instead of trying to grow the large single crystals required for conventional single-crystal X-ray diffraction, the material can be crystallized as a powder.
Sub-micron crystals within that powder can then be analysed by Electron Diffraction to determine the molecular structure.

2 — What if you don’t isolate the impurity at all?

In some cases, an impurity present at ~1% can be investigated directly within the product batch.
Instead of separating it first, we can examine the crystalline particles in the sample and scan for the “funny” one — a particle whose diffraction pattern is different from that of the target compound.
Once identified, that individual crystal can be analysed and its structure solved.

From one unusual particle to a complete molecular structure.

This is where Electron Diffraction becomes particularly powerful for impurity investigations:
🔹 Work with extremely small amounts of material
🔹 Investigate impurities as soon as they can be isolated during HPLC development
🔹 Avoid the challenge of growing large single crystals
🔹 And, in some cases, identify an impurity directly within the product batch, without prior separation

Does it replace MS or NMR?
No — and it shouldn’t. MS, NMR and diffraction provide complementary information.

But Electron Diffraction can provide something extremely valuable when conventional impurity investigations reach a bottleneck: a direct route to the molecular structure from crystals far too small for conventional X-ray diffraction.

Sometimes you don’t need more material.
You just need to look at a much smaller crystal.

ElectronDiffraction Impurity StructuralElucidation Pharma DrugDevelopment SolidState