Water Content is one of the key analytical aspects or properties in the Pharma field. It can be called Moisture content. The moisture content influences the physical properties of a substance such as weight, density, viscosity, refractive index, electrical conductivity, and many more.
Water content in pharmaceuticals
The Chemical, Thermogravimetric, and Loss on drying techniques can use to determine the Water Content or Moisture Content in the pharmaceutical industry.
Most natural and synthetic products contain moisture. The water content of a molecule or a product influences the below properties.
- Storability
- Agglomeration in the case of powders
- Microbiological stability
- Flow properties, viscosity
- Dry substance content
- Concentration or purity
- Commercial grade (compliance with quality agreements).
The below titration methods are widely used to determine the Water content (or) Moisture Content.
Water Content by Karl Fischer method (KF Titration)
The Karl Fischer Method determines moisture content in substances, utilizing the quantitative reaction of “water/moisture”. The KF reaction uses iodine and sulfur dioxide in the presence of lower alcohol such as methanol and an organic base such as pyridine, as shown in the above and below Formulae.
The titration can perform volumetrically or coulometrically.
Water Content by Volumetric method
Karl Fischer solution containing iodine is added until the first trace of excess iodine is present. The amount of iodine converted is determined by the burette volume of the iodine-containing Karl Fischer solution. Volumetric KF determinations are preferentially carrying between pH 4-7.
If the volumetric method is not suitable for the specified sample, proceed further with other operations.
Water Content by Coulometric method
The iodine participating in the reaction is generated directly in the titration cell by electrochemical oxidation of iodide until again a trace of unreacted iodine is detected. Faraday’s law can use to calculate the amount of iodine generated from the quantity of electricity required.
Coulometric KF titrations are preferable carrying within the pH range 4-7
The Karl Fischer titration is a moisture determination method specific for water and is suitable for samples with a high moisture content (titrimetry) and also for those with moisture contents in the ppm range (coulometry). Water by KF will give the complete water present if the sample is dissolved in the suitable solvent, whether it is hydrated or absorbed moisture. For the surface moisture, the sample need not be soluble, for eg. Ziprasidone HCl.
To know about the hydrated molecule it’s better to follow the TGA technique.
The moisture vaporization technique can use for thermally stable, insoluble solvents and one which reacts with the solvent used for KF.
Interferences and Selection of the method
The use of non-methanol containing Karl-Fischer reagent and solvent will reduce the interferences from Aldehydes and Ketones. Ammonia and amines can eliminate by the addition of Salicylic acid to the solvent. Other possible interferences to the KF reagent are certain active metals, metal oxides, metal hydroxides, chromates, melamine, etc.
The sensitivity and accuracy depend on several factors, particularly on the nature of the product.
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Water Content method selection and recommendations
For Aldehydes and Ketones, it is recommended to use Pyridine as the medium for the titration.
Whenever the water content for amines and ammonia is checked, it is recommended to add Salicylic acid to the solvent.
The sample size for analyzing the moisture content by KF
The amount of sample used depends on the anticipated water content and degree of accuracy. Please refer to the following convenient reference table.
| Sample water content as specification | Sample size |
| 20% and above | 0.01 g/0.2 ml |
| 2-10% | 0.2 g/ 0.5ml |
| 0.5%-1.0% | Min 1.0g/ 1.0 ml |
| 0.1%-0.5% | 2 g /2 ml |
The final consumed volume shall have acceptable precision and linearity against the sample size.
Unless otherwise specified in the individual monograph, accurately weighed or measured amount of the specimen test estimated to contain 10 to 250 mg of water in the selected uniform test sample.
Dried methanol is the preferred solvent; other suitable solvents may use for special or unusual test specimens.
Alkaline (NaOH, KOH, etc), and reductant samples are not suitable for water determinations by KF methods.
Other solvents like Glacial acetic acid, Dimethylformamide, Chloroform, and a mixture of solvents like Methanol and Pyridine, or non-interfering solvents can use.
The water content method shall validate for the API. The method validation parameters like precision, linearity, different chemist and analysis on a different day shall perform.
Note: Whenever you take a mixture of solvents, make sure that the methanol percentage will not be less than 50% of the mixture.
Standardization of the KF reagent
Quickly add 150 to 350 mg of disodium tartrate dihydrate into the titration vessel
Containing fresh methanol/dried methanol. Titrate to the endpoint. The water equivalence factor F in mg of water per ml is given by the formula.
F : 2(18.02/230.8) (W/V)
Where :
W : Wt of the sample disodium tartrate dihydrate in mg.
V : Volume of the regent consumed in ml.
Calculation of water content in the sample:
KF factor ‘F’ X Volume of KF reagent X 100
% Water content : ——————————————————–
Wt of the sample in grams
Precautions for KF Titration
The titration apparatus shall protect from atmospheric moisture by placing the silica gel or calcium chloride.
The water content of the sample shall be analyzed at the same temperature where the KF was standardized.
When the sample interferes with the Karl Fisher reagent, water in the sample can remove by heating and under a stream of nitrogen gas, and introduced into the titration vessel by using a water-evaporation device and establish the water content.
If any literature is available, follow the same.
As per the justification provided the method developed can be finalized.
Water Content method References
USP General Chapters and Assays – Water content USP <921>
Difference between Loss on Drying and Moisture Content
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