Water plays a crucial role in pharmaceutical products, being present at all stages of drug
development, manufacturing and storage. It can function as a solvent, an excipient or a by
product of a technological process and it significantly affects the physical, chemical and
microbiological properties of the final product. In solid dosage forms such as capsules, water
contributes to the integrity of the shell, elasticity and mechanical stability. Water in products
exists in different forms: free water, bound and adsorbed water – each influencing the
product's characteristics differently. Therefore, selecting an appropriate analytical technique
is essential for the accurate determination and interpretation of water content.
In the experimental part, we compared three analytical approaches for determining water
content: measurement of water activity, Karl Fischer titration in several variants (volumetric,
coulometric with a generator electrode and oven-based) and the loss on drying method. Each
method operates on a different principle and targets different form of water within the
sample. We aimed to evaluate which method is the most appropriate for determining water
content in capsules. All methods were validated with respect to repeatability, intermediate
precision, accuracy and robustness. Water activity measurement proved to be a suitable
technique for assessing free water in the samples. The method is fast, simple and does not
require complex sample preparation. Method validation confirmed the high repeatability,
accuracy and robustness of the results. In contrast, the Karl Fischer titration technique – both
volumetric and coulometric, despite their theoretical specificity for both bound and free
water, was not suitable in practice for capsule analysis. The primary limitation was the
reaction between the active pharmaceutical ingredient and the Karl Fischer reagent, which
led to incomplete water release. Finally, the water content was also determined using the
loss on drying method, during which the pharmacopoeial procedure for the active ingredient
was validated. However, this method may overestimate the water content, as it also measures
other volatile components. This was confirmed in our case, since the sample decomposed
under the drying conditions. Furthermore, the analytical procedure is time-consuming.
Based on the obtained results, water activity measurement proved to be the most optimal
method for determining the free water content in capsules, as it is fast, specific, and best
reflects the actual impact of water on the quality of the final product.
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