Application Notes

Pharmaceuticals

In the pharmaceutical field, Karl Fischer titration is an effective tool for precise moisture content measurement. Moisture content tends to be high, ranging from a few percent up to a few tenths of percent. For this reason, volumetric titration is generally used.

The provided examples show the application of Karl Fischer titration to biochemical and pharmaceutical products. Where the chemical ingredients of these products are known, direct titration can be used as it is possible to determine whether or not interference will occur. Even if products cause interference, they can still be measured using moisture vaporization and Karl Fischer titration, provided that they remain stable when exposed to heat.

The following examples are based on the actual implementation of these methods.

Biochemical Products
Pharmaceuticals
Chinese Herbal Medicines, Biological Tissues, Etc.

Biochemical Products - Key Points
Sugar-type dehydrated solvents are generally used when applying volumetric titration to biochemical products such as amino acids, nucleic acids, sugars, enzymes and lipids. Even substances that do not dissolve in general-use dehydrated solvents can be titrated directly using the appropriate dehydrated solvent, provided that the moisture content of the sample can be extracted adequately.

Direct coulometric titration is not suitable as many samples cannot be dissolved in the anolytes used for this type of titration.

Coulometric titration is carried out using the moisture vaporization method. Some samples break down at certain temperatures and there must be careful consideration of the temperature used for moisture vaporization.

L-lecithin and vitamin C react with the Karl Fischer reagent and cannot be titrated directly. Care is needed with general vitamin preparations that include vitamin C since these can also cause interference reactions. (Vitamin C reacts quantitatively with iodine. If the amount of vitamin C included in a sample is known, then the moisture content can be determined by adjusting the results.) Moisture vaporization is used with these substances.

Examples of Measurement
Volumetric Titration
Reagents used: Karl Fischer Reagent SS-Z, Dehydrated Solvent GEX, SU (or MS, FM) 25-50ml

Moisture Vaporization - Volumetric Titration
Reagents used: Karl Fischer Reagent SS-Z, Dehydrated Solvent GEX (or MS) + PG (3:1) 50-100ml

Moisture Vaporization - Coulometric Titration
Reagents used: Aquamicron AX (or AS) 150ml, Aquamicron CXU 10ml

Pharmaceuticals - Key Points

The Japanese Pharmacopoeia (7th revision) designates Karl Fischer methodology as the general testing method for 28 pharmaceutical products. In addition to volumetric titration, the coulometric titration and moisture-vaporization methods have also been specified. Normally, samples are placed in a general-use dehydrated solvent and stirred for a period before titration. Alternatively, surplus Karl Fischer reagent maybe added to the solution, which is then stirred for a period and reverse titrated with standard water-methanol. Depending on the solubility of the sample, a sugar-type or oil-type dehydrated solvent should be used. The chemical constituents of pharmaceutical products are usually known so it is possible to determine in advance whether or not a particular product is suitable for Karl Fischer titration. Coulometric titration is convenient when only a limited amount of sample can be obtained (such as when a substance is too valuable to use more than a few milligrams), or when moisture content is low. The moisture vaporization method is used when it is difficult to draw the moisture into the dehydrated solvent, or when interference would occur. As with other types of substances, the heating temperature must be selected with care. Moisture vaporization should be used only after careful consideration.

Examples of Measurement
Volumetric Titration
Reagents used: Karl Fischer Reagent SS-Z (or SS), Dehydrated Solvent SU (or MS, FM) 25-50ml

Moisture Vaporization - Volumetric Titration
Reagents used: Karl Fischer Reagent SS-Z , Dehydrated Solvent GEX (or MS) + PG (3:1) 50-100ml

Moisture Vaporization - Coulometric Titration
Reagents used: Aquamicron AX (or AS) 100ml, Aquamicron CXU 5ml

Moisture Vaporization - Coulometric Titration
Reagents used: Aquamicron AX (or AS) 150ml, Aquamicron CXU 10ml

Chinese Herbal Medicines, Biological Tissue, etc. - Key Points
Either a general-use or a sugar-type dehydrated solvent is used for Chinese herbal medicines. In general, however, these products are difficult to dissolve. This means that insufficient moisture is extracted and accurate analytical results cannot be obtained. The moisture vaporization method is used for this reason. The heating temperature must be considered carefully as heating can cause some products to change color or break down. In the examples below, biological tissue was dispersed in a general-use dehydrated solvent and subjected to Karl Fischer titration. Similar procedures should be used for capsules and other biological tissues.

Examples of Measurement
Volumetric Titration
Reagents used: Karl Fischer Reagent SS-Z (or SS), Dehydrated Solvent GEX, SU (or MS, FM) 25-50ml

Moisture Vaporization - Volumetric Titration
Reagents used: Karl Fischer Reagent SS-Z (or SS), Dehydrated Solvent GEX (or MS) + PG (3:1) 50-100ml

Moisture Vaporization - Coulometric Titration
Reagents used: Aquamicron AX (or AS) 150ml, Aquamicron CXU 10ml