Karl Fischer versus Loss-On-Drying

Several methods are available to determine the water content of a substance, among which, loss-on-drying (LOD) and Karl Fischer titration are commonly used to determine the moisture content in pharmaceuticals.


LOD is a time-honored method which is the basis for several standard quality control specifications. It consists of heating the sample to achieve complete drying, while keeping the temperature below melting point. This is accomplished in various ways such as drying ovens, infrared balances, and infrared lamps. The drying conditions are strictly specified. The difference in weight after drying is due to the loss of all evaporated matter, which is taken to represent the moisture content.

The difficulty is that this technique measures all the moisture lost from the sample, which includes not just water but also any other volatile component already present in the sample (like residual volatile solvents) or created by polymerization or degradation of the sample.

The repeatability and accuracy of the results demand that strict temperature and time controls be followed. Finally, several hours may be required to dry the sample by normal methods, which can lead to a slowdown of the workflow at that point, as when it is being used in quality control processes during product manufacture.

LOD is comparable in accuracy to other methods provided the sample is very pure and contains only minute amounts of volatile impurities. Sometimes, the heating may fail to volatilize all such impurities or to release the water of crystallization.


The disadvantages of LOD include:

  • Prolonged process
  • Does not determine water content  specifically
  • Requires careful setting of the temperature and period of heating for each sample, to avoid melting or degradation of the sample, and the results are specific to the settings
  • Water of crystallization may not be released by heating
  • Environmental influence on the results may be significant
  • The accuracy of weighing affects the results

Karl Fischer (KF) Titration

Karl Fischer titration is a very specific determination method which detects and measures only water, including water of crystallization and surface-absorbed water. It is based upon a redox reaction involving water and iodine in the presence of a base, an alcohol, and sulfur dioxide. The water-iodine reaction is dependent upon the presence of water, and therefore the titer of reagent used up in the reaction reflects the amount of water in the sample as there is no other source of water.

The KF reagent contains iodine and when it has completely reacted with the total water, excess iodine appears in the solution, causing a color change as well as an electrometric change which can be detected by a double platinum electrode. KF titration measures total water and is not affected by the presence of residual volatile solvents. It has a wide and sensitive range of determination from a water content of 100% to 1 ppm.


The advantages of the KF method include:

  • Specificity for water
  • High sensitivity for measurement of even minute amounts of water as in gases or in some plastics
  • Wide range of water determination
  • Measures the total water in the sample
  • Coulometric KF determination is an absolute method, which means there is a strictly quantitative relationship between the current consumed in generating iodine and the total sample water, yielding highly precise measurements


The limitations of this method include:

  • It is best suited for liquids
  • Solids must be dissolved in an appropriate alcoholic solvent and this may require physical preparation of the sample such as powdering/ grinding of the sample, modification of the reagent, and warming of the cell
  • All substances are not easily dissolved in the specific KF reagents used

Comparing LOD with KF Titration

The comparability of the LOD and KF methods is restricted by the fact that they measure different things using different methods. The LOD is based on physical mass determination after the escape of volatilized moisture, including fats and water. KF titration is a chemical reaction with the water in a sample. However, identical values are returned with either method if water is the only moist component of the sample, if it is present in an easily-released form, and if the sample is thermally stable, preventing the release of more water by polymerization or breakdown. This includes carboxylic acid and some mineral salts.

LOD is still the method mentioned in many pharmaceutical and food substance specifications, for historical reasons. However, in these substances, which are often complex mixtures of volatile organic substances, fats and water, among other things, LOD gives different results from KF titration. Falsely high values may be obtained with foodstuffs when compared with those obtained by KF titration because at the temperatures required for drying, the foodstuff breaks down.

The chemical composition of the substance to be tested by LOD must be known very well. If it is a hydrate it may be necessary to find the weight of the anhydrous equivalent. Information about absorbed moisture must be taken into account to weigh the correct amount of the substance so as to get the required amount of anhydrous substance.

In short, LOD is preferred for very pure samples with low levels of volatile impurities and significant moisture content. If the sample contains more than traces of alcohols or other sources of moisture, water determination is better done using the KF method for its specificity. If only very low amounts of water are present, it is an indication for the use of KF titration for its sensitivity.

What is a Moisture Analyzer and How Does it Work?

Further Reading

Last Updated: Jul 18, 2023

Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.


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