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Karl Fischer Reagent and Its Reactions

Karl Fischer reagent method of water content determination is widely used in pharmaceuticals and other manufacturing industries. This is most reliable and accurate method for moisture determination.
You are given a sample with a trace amount of water and you need to determine the amount of water in the sample, what do you do? The method to use is the Karl Fischer (KF) moisture analysis. Karl Fischer method uses the Karl Fischer Reagents to determine the moisture content of a sample and it is a widely popular method because it allows you to determine the water content of drug in a very fast, accurate and specific way in addition to needing a very small amount of sample for the analysis.

What is the Karl Fischer Reagent?
The reagents consist of a solvent Alcohol (ROH), a known concentration of Iodine (I2), a Base (RN) and Sulfur dioxide (SO2).

Principle of Reaction
Karl Fisher ReagentThe Bunsen reaction between iodine and sulfur dioxide in an aqueous system is the basis for the Karl Fischer Reagents reactions.

I2 + SO2 + 2H2O => 2HI + H2SO4

The above reaction was adjusted by Fischer for the determination of water content of a substance in a non-aqueous system.

When you titrate the KF reagents in a titration cell, the following reactions take place:

The first reaction is that between iodine and sulphur dioxide in the presence of a neutralizing base to form an alkyl sulphite intermediate. The common base used in Karl Fischer titration is pyridine, primary amines such as imidazole can also be used.

ROH + SO2 + RN => [RNH]SO3R

The alkyl sulphite is then oxidized by iodine to an alkyl sulphate, it is this oxidation reaction which consumes water that is used for water content determination.

[RNH]SO3R + H2O + I2 +2RN => 2[RNH]I + [RNH]SO4R

Once all the water present have been used up, you can determine the end point of the reaction by detecting the presence of excess iodine using constant-current polarization voltage method which detects a sharp voltage drop near the endpoint.

You can use the Karl Fischer reagents in both Volumetric and Coulometric titrations.
In the Volumetric Titration, you use a KF Solution containing dissolved iodine as the titrant until the presence of a trace excess iodine is detected at the endpoint. You determine the amount of water by measuring the iodine required to react with the water content in your sample as read from the burette volume of the Karl Fischer solution. You can use this method to determine the moisture content of a sample in a range of 100 ppm to 100%.

In the Coulometric procedure, you add your sample to an electrolytic solution consisting of iodide ions and other KF reagents. You then observe the production of iodine from the electrolytic oxidation of iodide ions as you titrate. The iodine produced in this reaction is proportional to the quantity of electricity required for the oxidative conversion of iodide ions into iodine up to the end point (presence of a trace of excess iodine). This method can determine a sample’s water content in the 1 ppm to 5% range.

Limitations and Precautions:
You should not use the KF reagents for samples containing redox-active constituents such as dimethyl sulfoxide because the constituents may react with the reagents and give incorrect results. In addition, you must carefully dry the titrating vessel before use.

The Karl Fischer Reagents method is a highly selective and reliable means of determining the moisture content of substances even when present in trace amounts.

Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of pharmaguideline.com, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
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