Water determination in pharmaceuticals

The Karl Fischer (KF) Oven Method permits the accurate, precise and straightforward determination of the water content of pharmaceuticals that are not amenable to direct KF titration

Quality and shelf life of active pharmaceutical ingredients depend primarily on the content of adsorbed (surface water) or bound water (water of crystallisation).

Although the 4th Edition of the European Pharmacopeia (2002) describes the direct Karl Fischer (KF) Titration as the most important method for determining the water content, in some cases, where substances undergo side reactions with the KF reagents or where they release their water only at high temperatures, the European Pharmacopeia recommends the quantification via the loss on drying (LOD) in a drying cabinet or desiccator.

However, besides the water to be determined, this method also includes all volatile compounds (e.g impurities, degradation products) released at higher temperatures.

The KF Oven Method allows to resolve the above-mentioned problems.

Depending on the water content of the sample, the KF titration can be performed either volumetrically for higher, or coulometrically for lower, water contents.

Considering the relatively small amount of water in most pharmaceuticals, samples were analysed coulometrically.

The calculation of the sample water content involves also the determination of the humidity in the sample vessel and the moisture adhering to the vessel surface, vial cap and septum.

Three empty but sealed sample vials are analysed under the same conditions as the particular sample.

The resulting mean value is stored as a blank value and automatically taken into account in the calculation.

Subsequently a threefold determination for each compound is performed.

Accuracy of the KF titrations is checked at regular intervals with a certified KF oven standard.

Water release curve for metamizole sodium.

The optimum oven temperature for driving off the water should ensure complete water extraction in a reasonable time excluding decomposition of the sample.

This means that the oven temperature should be chosen as high as possible to ensure short determination times, but still be 20 to 30C below the decomposition temperature.

The oven temperatures for unknown samples are determined on the basis of the water-release curves that were recorded for all investigated pharmaceuticals in the temperature range 50 to 250C.

Comparison KF Oven Method/LOD.

In contrast to the wide range of the recovery rates for the loss on drying (LOD) specified by the European Pharmacopoeia (60...120%), the KF oven method provides recovery rates between 90 and 110%.

Additionally, the water content is determined with an excellent repeatability in less than 12 minutes.

Advantages of the KF Oven Method .

The Oven Sample Processor.

* enables accurate and precise analysis of pharmaceuticals that formerly were not amenable to KF titration.

* avoids contamination of the oven and titration cell; consequently there are no carryover and memory effects.

* works non-destructively and requires only 15...30 mg of the potentially expensive pharmaceutical.

* allows recording of water release curves providing information about the kinetics of the water release.

* Significantly reduces manual sample preparation steps.

* Enhances sample throughput (high efficiency).

* Analyses all samples under identical and reproducible conditions, providing results of the highest precision.

Water determinations carried out with several pharmaceuticals demonstrate that the values obtained with the KF Oven Method all lie within the ranges specified in the European Pharmacopoeia.

Moreover, the automated KF Oven Technique significantly enhances sample throughput and repeatability of the results.

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