The Wet-Chemistry Workhorses — Karl Fischer, Titrimetry, Ion Chromatography
Not everything on a small-molecule specification is an LC method. These tests are on almost every one of them, and — Karl Fischer especially — among the most-run assays in a QC lab.
The one idea
These four tests answer questions an LC–UV method structurally can’t: how much water, how much total volatile content, how much inorganic residue, and how much of a small ion that never gives a useful chromophore.
The wet-chemistry workhorses
| Test | Method | Measures |
|---|---|---|
| Water content | Karl Fischer (volumetric / coulometric) | Water, specifically — not total volatiles (that’s LOD) |
| Loss on drying (LOD) | Gravimetric | Total volatiles |
| Residue on ignition / sulfated ash | Gravimetric | Inorganic residue |
| Assay / content of a salt or counterion | Potentiometric titration; ion chromatography | Acid/base content; specific counterions and small ions |
Why ion chromatography belongs here, and belongs to chromatography
Ion chromatography separates ions on a column by ion-exchange retention, exactly the competition between stationary and mobile phase that opened this session — it just detects by conductivity rather than UV, and it resolves species (chloride, sulfate, small organic acids, counterions) that give an LC–UV method little or nothing to see. It sits in this “wet chemistry” group by purpose — it’s finishing the same job as a titration — while sitting in chromatography by mechanism.
Karl Fischer — the fine print
Volumetric KF suits higher water levels; coulometric KF reaches much lower levels (ppm) without a burette. Either way, the result is only as good as the titer (KF reagent’s water-equivalence factor), which drifts and must be checked routinely, and the sample-introduction technique — a sample that isn’t fully dissolved or that absorbs atmospheric moisture during handling will bias the result before the titration even starts.
Where the analyst sits
Karl Fischer titration is one of the most-run tests in a QC lab and one of the easiest to get subtly wrong — reagent titer drift and sample-introduction technique are common early competency checks, not edge cases. And a discrepancy between Karl Fischer and loss-on-drying is not a contradiction to explain away: they are measuring different things, and the gap between them is itself informative about what else is volatilising.
For discussion
- Karl Fischer and loss-on-drying give different numbers for the same sample. Which is right, and what does the difference tell you?
- A coulometric Karl Fischer result drifts upward over a week of use with no change in sample type. What would you check first?
- Why is ion chromatography, and not LC–UV, the default method for a chloride or sulfate counterion assay?
Source note. Compendial basis: USP ⟨921⟩ (water determination), ⟨281⟩ (residue on ignition), ⟨731⟩ (loss on drying); Ph. Eur. 2.5.12 (water: semi-micro determination), 2.2.47 (ion chromatography).