Determination of water content in pharmaceutical products according to GLP: Karl Fischer and loss-on-drying methods
The water content in pharmaceutical products is a parameter that directly affects the product's stability, shelf life, and efficacy. The moisture content of a drug influences the rate of chemical degradation, the risk of microbial growth, and physical properties such as flowability and tablet hardness. Therefore, GLP-compliant water determination in pharmaceutical products is an essential component of quality control.
Water determination performed according to Good Laboratory Practice (GLP) ensures that the results are reliable, traceable, and acceptable to international regulatory authorities. This article will discuss the importance of determining the water content in pharmaceutical products, the fundamental methods used, and Nano-Test's GLP-compliant services in this area.
The importance of water content in pharmaceutical products
Water can be both a desirable and an undesirable component in pharmaceutical products. Some active pharmaceutical ingredients exist in hydrated form, with water molecules being an integral part of the crystal structure. However, free water (adsorbed moisture) generally poses a risk to product stability [citation: 6].
The most important reasons for controlling the water content:
- Chemical stability: Hydrolysis-sensitive active ingredients (e.g., aspirin, penicillins) decompose rapidly in the presence of moisture.
- Microbiological safety: High water activity promotes the growth of bacteria and molds. ICH Q6A links the need for microbiological limit tests to the "dryness" of the product [quote: 6].
- Physical properties: Moisture affects the flowability of powder, tablet hardness and dissolution rate [Quote:12].
- Shelf life: The water content determines the product's degradation profile over time.
Basic analytical methods for water analysis
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 determining the water content in pharmaceutical products. The Karl Fischer reaction is based on the quantitative reaction of iodine and sulfur dioxide in the presence of water [citation: 13].
There are two basic variants:
- Volumetric Karl Fischer method: Suitable for samples with high water content (> 0.1%). The amount of water is calculated by measuring the titrant volume [citation: 1].
- Kulometrische Karl-Fischer-Methode: Ideal für die Bestimmung von Spurenwasser (< 0,1 %). Die durch Elektrolyse erzeugte Jodmenge wird gemessen [Zitat:4].
The Karl Fischer method provides the most reliable results because it is specific to water and is not affected by other volatile substances [Quote:20].
2. Loss on Drying (LOD)
In this method, the sample is dried at a specific temperature (usually 100–105 °C) until it reaches constant weight, and the weight loss is calculated as a percentage [Quote:8][Quote:14].
The loss-on-drying method measures not only water, but also volatile solvents and other volatile components. Therefore, the result may be higher than the actual water content [Quote:20].
3. Thermogravimetry (TGA)
Thermogravimetry measures the change in weight of a sample under a controlled temperature program. It is an alternative method for substances for which the Karl Fischer method is not applicable (due to solubility problems) [citation: 4].
| Proceedings | principle | Suitable water area | Advantages | restrictions |
|---|---|---|---|---|
| Karl Fischer (volumetric) | Iodine-water reaction, measurement of titrant volume | >0.1% (high water content) | Specifically designed for water, high accuracy | Not applicable to substances with solubility problems. |
| Karl Fischer method (colorometric) | Iodine production by electrolysis | <%0,1 (Spurenwasser) | Ultra-low detection limit, small sample size | Not suitable for high water content |
| Loss on Drying (LOD) | Drying to constant weight, weight loss | Wide measuring range | Simple, inexpensive, widely used in the pharmacopoeia | Not specific to water, 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 ICH guidelines
The determination of water content in medicinal products is described in detail in the monographs of the pharmacopoeias (Ph. Eur., USP, JP). The Karl Fischer method is recognized as the reference method by the European Pharmacopoeia (Ph. Eur.) and the US Pharmacopoeia (USP) [citation:5][citation:10].
The ICH Q6A guideline provides a framework for setting water content specifications for new active pharmaceutical ingredients and medicinal products [citation: 6]. The guideline points out that the product's "dry matter content" can be used to determine the need for microbiological limit tests.
GLP-compliant services for water content determination using nano-testing
The water content of your pharmaceutical products is a crucial component of both quality control and the regulatory approval process. Nano-Test , with its comprehensive water content determination services in GLP-accredited laboratories, is a reliable solution partner for the pharmaceutical industry [citation:5][citation:9].
Nano-Test – Statement of Work
Nano-Test offers GLP-compliant water content determination services for pharmaceutical products. Our service portfolio includes:
- Karl Fischer titration: Precise determination of water concentration over a wide range using volumetric and coulometric methods. Fully compliant with the monographs of the Ph. Eur. and USP [citation: 5].
- Loss on drying (LOD): Determination of water and volatile components by drying to constant weight at the temperatures and times specified in the pharmacopoeia monographs [citation:8].
- Thermogravimetry (TGA): Alternative solution for substances for which the Karl Fischer method is not applicable [Quote:4].
- Method validation: ICH Q2(R2)-compliant method development and validation tailored to your product matrix.
- Pharmaceutical water analyses: Analysis of purified water (Ph. Eur. 0008), water for injection (Ph. Eur. 0169) and other pharmaceutical water qualities [citation:16].
All our analyses are presented in the form of GLP compliance reports , which have an inspection authorization and guarantee data integrity (ALCOA+ principles).
Advantages of nano-testing in determining water content:
- GLP accreditation: Laboratory infrastructure with OECD GLP conformity declaration [Quote:9][Quote:15].
- Expertise in two methods: both volumetric and coulometric Karl Fischer titrators.
- Pharmacopoeia compliance: Test protocols that are fully compliant with the monographs of Ph. Eur., USP and JP.
- Fast reporting: Results delivered within 3–5 working days for standard water analysis.
- Expert 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 product's stability, safety, and efficacy. While Karl Fischer titration remains the reference method due to its specific structure and high accuracy, loss-on-drying titration and thermogravimetry offer alternative solutions in certain cases.
Nano-Test, with its GLP-accredited laboratories, advanced analytical infrastructure, and expert staff, fully meets the water content determination requirements of pharmaceutical manufacturers. Partner with Nano-Test to improve the quality of your products and accelerate their time to market.