Determination of the water content in pharmaceutical products according to GLP: Karl Fischer and Drying Loss Methods
The water content in pharmaceutical products is a parameter that directly affects the stability, durability and effectiveness of the product. The moisture content of a drug influences the rate of chemical degradation, the risk of microbial growth and physical properties such as flow properties and tablet hardness. Therefore, the GLP-compliant water determination in pharmaceutical products is an indispensable component of quality control.
The water determination carried out as part of the good laboratory practice (GLP) ensures that the results are reliable, traceable and acceptable for international supervisory authorities. In this article, we will cover the importance of determining the water content in pharmaceutical products, the basic methods used, and the GLP-compliant Nano-Test services in this area.
The importance of water content in pharmaceutical products
Water in pharmaceutical products can be both a desirable and undesirable ingredient. Some active ingredients are in hydrated form, with water molecules being an integral part of the crystal structure. However, free water (adsorbed moisture) usually poses a risk of product stability [quote:6].
The main reasons for controlling the water content:
- Chemical stability: Hydrolysis-sensitive active ingredients (e.g. aspirin, penicillins) decompose quickly in the presence of moisture.
- Microbiological Safety: High water activity promotes the growth of bacteria and molds. I Q6A attaches the need for microbiological limit checks to the "degree of dryness" of the product [quote:6].
- Physical properties: Moisture affects the fluidity of powder, tablet hardness and dissolution rate [quote:12].
- Durability: The water content determines the decay profile of the product over time.
Basic analytical methods for water determination
Three basic methods are used to determine the water content in pharmaceutical products. The choice of method depends on the properties of the substance to be analyzed and the requirements specified in the pharmacopoeia monograph.
1. Karl Fischer Titration
It is considered the Gold Standard for water determination in pharmaceutical products. The Karl Fischer reaction is based on the quantitative reaction of iodine and sulfur dioxide in the presence of water [quote:13].
There are two basic variants:
- Volumetric Karl Fischer Method: Suitable for high water content samples (> 0.1%). The amount of water is calculated by measuring the volume of the titrant [quote:1].
- Kulometric Karl Fischer Method: Ideal for the determination of trace water (<0.1%). The amount of iodine generated by electrolysis is measured [quote:4].
The Karl Fischer method provides the most reliable results as it is specific to water and not affected by other volatile substances [quote:20].
2. Loss of Drying (Loss on Drying - LOD)
In this method, the sample is dried to constant weight at a certain temperature (usually 100-105°C) and the weight loss is calculated as a percentage [quote:8][quote:14].
The drying loss method not only measures water, but also volatile solvents and other volatile components. Therefore, the result can be higher than the actual water content [quote:20].
3. Thermogravimetry (TGA)
Thermogravimetry measures the weight change of the sample under a controlled temperature program. It is an alternative method for substances where the Karl Fischer method is not applicable (due to solubility problems) [Quote:4].
| Act | Principle | Suitable water area | Advantages | Limitations |
|---|---|---|---|---|
| Karl Fischer (volumetric) | Iodine water reaction, measurement of titrant volume | >0.1% (high water content) | Especially for water, high accuracy | Not applicable to substances with solubility problems |
| Karl Fischer Method (Colometric) | Iodine generation by electrolysis | <%0.1 (Trace water) | Ultra-low detection limit, small amount of sample | Not suitable for high water content |
| Drying Loss (LOD) | Drying to constant weight, weight loss | Wide measuring range | Simple, inexpensive, widely used in the pharmacopoeia | Not water specific, also measures volatile substances |
| Thermogravimetry (TGA) | Weight change at controlled temperature | Wide measuring range | Alternative to the Karl Fischer method, no resolution problem | Not water specific, requires interpretation |
Pharmacopoeia Requirements and I-Guidelines
The determination of the water content in drugs is described in detail in the monographs of the pharmacopoeias (Ph. Eur., USP, JP). The Karl Fischer method is recognized by the European Pharmacopoeia (Ph. Eur.) and the US Pharmacopoeia (USP) as a reference method [quote:5][quote:10].
The ICH Guideline Q6A provides an orientation framework for setting water content specifications for new active ingredients and drugs [Quote:6]. The guideline points out that the "dry content" of the product can be used to determine the need for microbiological limit checks.
GLP-compliant water content determination services with Nano-Test
The water content of your pharmaceutical products is a crucial component of both quality control and the approval process. Nano-Test is a reliable solution partner for the pharmaceutical industry with its comprehensive water content determination services in GLP-accredited laboratories [Citation:5][citation:9].
Nano-Test – Performance Description
Nano-Test offers GLP-compliant water content determination services for pharmaceutical products (Water Content Determination) for pharmaceutical products. Our service portfolio:
- Karl Fischer titration: Precise water determination over a wide concentration range using volumetric and coulometric methods. Fully compliant with Ph. Eur. and USP monographs [quote:5].
- Drying loss (LOD): Determination of water and volatile components by drying up to constant weight at the temperatures and times given in the pharmacopoeia monographs [quote:8].
- Thermogravimetry (TGA): Alternative solution for substances where the Karl Fischer method is not applicable [quote:4].
- Method Validation: I Q2(R2) compliant method development and validation tailored to your product matrix.
- Pharmaceutical water analyzes: Purified water analysis (Ph. Eur. 0008), water for injections (Ph. Eur. 0169) and other pharmaceutical water qualities [quote:16].
All of our analyzes are presented in the form of GLP Conformity Reports, which have an inspection permit and ensure data integrity (ALCOA+ principles).
Advantages of Nano-Test in determining the water content:
- GLP accreditation: Laboratory infrastructure with OECD-GLP declaration of conformity [quote:9][quote:15].
- Competence in two methods: Both volumetric and coulometric Karl Fischer titrators.
- Pharmacopoeia Conformity: Test protocols fully compliant with the monographs of Ph. Eur., USP and JP.
- Fast reporting: Delivery within 3-5 working days for standard water determination analysis.
- Specialist team: A team of chemists with experience in pharmaceutical analysis and validation.
Determining the water content in pharmaceutical products is a crucial quality parameter for the stability, safety and effectiveness of the product. While the Karl Fischer titration continues to be the reference method due to its specific structure and high accuracy, drying loss and thermogravimetry offer alternative solutions in certain cases.
With its GLP-accredited laboratories, its advanced analytical infrastructure and its specialist staff, NANO-TEST comprehensively meets the requirements of pharmaceutical manufacturers for water content determination. Collaborate with Nano-Test to increase the quality of your products and accelerate their market launch.