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The interference of penicilloic acids with Karl Fischer titration of penicillins
J Hoebus1, E Roets, J Hoogmartens
1Laboratorium voor Farmaceutische Chemie en Analyse van Geneesmiddelen, Faculteit Farmaceutische Wetenschappen, Katholieke Universiteit Leuven, Belgium.
Abstract:
Phenoxymethylpenicilloic acid monohydrate was titrated with 12 different brands of Karl Fischer reagent. It was shown that only the four pyridine-containing reagents gave correct results for water content, providing that the sample solution was cooled in an ice bath or that the delay time of the amperometric end-point determination was 10 s instead of 30 s, as prescribed by the European Pharmacopoeia. The other reagents always gave results, which were too high. When these reagents were used to titrate the water in sodium amoxicillin, sodium carbenicillin or sodium ticarcillin the same conclusions could be drawn with regard to the accuracy of the results, the usefulness of the reagents and the reaction conditions. These penicillins may contain up to 9% penicilloic acids. The maximum relative error obtained with pyridine-free reagents was about 50% for ticarcillin. It has been confirmed that penicilloic acids interfere with Karl Fischer titration of water and that this interference is greatly dependent on the brand of reagent and on the reaction conditions.
Insights
Karl Fischer titration accuracy for water content in penicillins is affected by penicilloic acids. Pyridine-containing reagents and specific conditions ensure accurate results, unlike other reagents causing high water content readings.
Area of Science:
- Analytical Chemistry
- Pharmaceutical Analysis
Background:
- Accurate water content determination is crucial for pharmaceutical quality control.
- Penicillins, like amoxicillin and carbenicillin, can contain significant amounts of penicilloic acids.
- Penicilloic acids are known to potentially interfere with Karl Fischer titration.
Purpose of the Study:
- To evaluate the accuracy of Karl Fischer reagents for water determination in penicillins.
- To investigate the interference of penicilloic acids in Karl Fischer titration.
- To identify optimal conditions and reagent types for accurate water content analysis in penicillins.
Main Methods:
- Titration of phenoxymethylpenicilloic acid monohydrate using 12 different Karl Fischer reagents.
- Titration of water content in sodium amoxicillin, sodium carbenicillin, and sodium ticarcillin.
- Comparison of results using pyridine-containing and pyridine-free Karl Fischer reagents.
- Evaluation of reaction conditions, including sample cooling and amperometric end-point delay time.
Main Results:
- Only pyridine-containing Karl Fischer reagents yielded accurate water content results.
- Accurate results with pyridine-containing reagents required sample cooling or a 10s delay time for amperometric end-point determination.
- Pyridine-free reagents consistently overestimated water content, with errors up to 50% for ticarcillin.
- Penicilloic acids were confirmed to interfere with Karl Fischer titration, with interference varying by reagent and conditions.
Conclusions:
- The brand of Karl Fischer reagent significantly impacts the accuracy of water determination in penicillins.
- Pyridine-containing reagents are recommended for accurate Karl Fischer titration of water in penicillins.
- Optimized reaction conditions, including sample temperature and end-point determination timing, are essential to mitigate interference from penicilloic acids.