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Quality Control >> Raw Materials and Excipient Testing >> Water Determination by Karl Fischer

Water Determination by Karl Fischer

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Karl Fischer

Karl Fischer titration has become one of the most widely used techniques for the determination of water content in a variety of substances. Many pharmaceutical products contain water in adsorbed form, and as a result, the determination of the water content is important in demonstrating compliance with the regulatory standards.

Eurofins BioPharma Product Testing offers significant capacity using the latest Karl Fischer technology, which offers analytical advantages. In particular, the Karl Fischer Oven Determination has become our platform approach for new moisture testing methods.

Why Choose Eurofins BioPharma Product Testing?

  • We have more than 15 years of experience developing and executing methods for water determination by Karl Fischer analyses.
  • We have completed a significant amount of water determination testing using multiple types of instrumentation.
  • We offer quick turnaround time on method development and validation for Karl Fischer testing (in as little as two weeks).
  • All Testing is performed in humidity controlled laboratories, eliminating moisture contaminations from the ambient environment.

Key Factors

A critical step in determining the most appropriate analytical approach is to address the following key factors:

  • Expected water content of the material
  • The amount of material available for analysis
  • Thermodynamic properties of the material
  • Material solubility information
  • Chemical structure of the compound/material

Approaches

Karl Fischer Oven Determination

  • Material is required to be thermodynamically stable.
  • Requires about 50 mg to 300 mg of material.
  • Avoids contamination of the oven and titration cell: minimal side reaction effects.
  • Significantly reduces sample preparation steps.
  • Significantly enhances sample throughput, accuracy and repeatability of results.

Volumetric Karl Fischer Determination

  • Best suited for materials with at least 1% water and the test article should contain 1 to 100 mg of water.
  • Karl Fischer reagents contain the sulfur dioxide, iodine, base and solvent necessary for USP <921> direct titration (Method 1a). The apparatus is designed for accurate determination of moisture content.
  • The endpoint is determined potentiometrically. This method is best used for Drug Products that do not easily dissolve.

Coulometric Karl Fischer Determination

  • Best suited for materials with less than 1% water or projects with limited sample availability.
  • The test article should contain 0.2 to 10 mg of water.
  • A sample extraction procedure is preferred.
  • The same reaction used for volumetric KF analysis is used for coulometric KF analysis; however, rather than adding a volumetric solution, iodine for the reaction is produced by anodic oxidation in an iodide-containing solution within the titration vessel.
  • When all the water in the test article has been consumed, an excess of iodine occurs, which is detected electrochemically, thus indicating the endpoint.
  • This method is well suited for API’s that readily dissolve in reagents.

Other Considerations for Method Validation

Specificity

  • Spiked accuracy experiments not recommended due to limitations of accuracy/technique with spiking.

Quantitation Limit (QL)

  • For the most accurate titrations, methods should be designed so the samples utilize a minimum of 10% of the burette (Volumetric), or 200 μg (Coulometric). If this is not possible, a Quantitation Limit reporting level can be established using lower values during validation, however the actual moisture content that the Quantitation Limit Level will depend on the material and method set-up.

Linearity and Range

  • For volumetric Karl Fischer titration, linear titration is a function of the instrument performance, rather than the sample analysis method, and therefore linearity experiments are deemed un-necessary. For coulometric Karl Fischer titration, the qualitative relationship between the current and iodine allows for the absolute dosing of iodine, and therefore linearity experiments are deemed unnecessary. A semi-annual instrument performance qualification is performed, which includes instrument accuracy, precision and linearity.
  • A robustness study may replace a method linearity and range experiment, which challenges sample amount or extraction and injection volumes. The robustness study is generally designed such that 50%-150% of the nominal sample amount is titrated.

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