All4Nutra
Abstract
Fluid co-administered with oral medication directly affects its behaviour. Often, people use fluids other than water when taking their medications. Capsules (mainly gelatine– and HPMC-based) are widely used solid oral dosage forms. The presented study aimed to investigate the behaviour of gelatine and HPMC capsules in several fluids in vitro and in vivo. The second aim was to assess the influence of administered fluids on the gastric emptying. The third aim was to assess the usability and predictive power of different in vitro methods for drug analysis and compare them with in vivo data.
Highlights
- GastroDuo demonstrated better predictive power than the USP 2 apparatus.
- In vitro real-life fluids influenced capsules behaviour more than in vivo.
- HPMC capsules were not influenced by temperature or black tea in vivo.
- Temperature affected the opening times of gelatine capsules in vivo.
- Warm and cold water and warm black tea did not influence gastric emptying.
For in vitro studies, two systems with different complexities were used: the compendial USP 2 apparatus and the GastroDuo biorelevant model. In both systems, 25 mL of SGF and 240 mL of tested fluid were used. To obtain the in vivo data, a clinical study with 12 young and healthy volunteers was performed. In this study, the salivary tracer technique, which utilises caffeine kinetics as a marker of a dosage form behaviour in the GIT, was used. In vitro, the temperature strongly affected the opening times of gelatine capsules (rapid opening in warm media and slower in cold). In vivo, the opening time of gelatine capsules in warm black tea was slightly delayed in comparison to warm water. The differences in opening times between warm and cold water and warm black tea and cold water were significant. In USP 2 Apparatus, HPMC capsules were more sensitive to the tested media than in the biorelevant GastroDuo model.
There were no significant differences in the opening times of HPMC capsules in vivo. Gastric emptying of warm water, cold water or warm black tea was not affected, suggesting that the altered in vivo absorption kinetics was caused by the in vivo behaviour of the capsules, depending on their properties and not by changes in the gastric emptying of the co-administered fluids. The presented study allows a better understanding of gelatine and HPMC capsules behaviour in vitro and in vivo administered with different fluids. Moreover, it demonstrated the relevance of in vivo data as well as the limitations of in vitro tools.
Download the full article as PDF here The effect of black tea and water temperature on the disintegration of gelatine and HPMC capsules, tested with the paddle device, GastroDuo and in vivo pharmacokinetics
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2. Materials and methods
2.1. Capsules for in vitro experiments and clinical study
In this study, hard gelatine (Capsugel® Coni-Snap®, Capsugel Belgium, Bornem) and HPMC (Capsugel® Vcaps® Plus, Capsugel France, Colmar) capsules were used. Both capsules were size 0 and a natural transparent colour. A batch of powder mixture was prepared from the substances listed in Table 1. Each capsule (for in vitro and in vivo studies) was filled manually with 250 mg of the powder mixture with 1 % allowed variation. For the in vivo study, capsules contained the same ingredients, except caffeine, which was an isotope-labelled 13C1 caffeine.
Table 1. Composition of the powder mixture for capsule filling.
| Ingredient | Manufacturer In vitro/in vivo | Quantity per one capsule (mg) | Quantity % | |
|---|---|---|---|---|
| Caffeine (12C/13C1) | Caelo, Hilden, Germany | Eurisotop a Cambridge Isotope Laboratories Company, Cambridge, MA, USA | 25.000 | 10.000 |
| Microcrystalline Cellulose (Pharmacel 102) | DFE Pharma, Goch, Germany | 223.875 | 89.550 | |
| Colloidal silicon dioxide (Aerosil® 200) | Fagron, Glinde, Germany | 1.125 | 0.450 |
2.2. Coated tablets for evaluation of gastric emptying
The coated tablets consisted of a core and a pressed coating. The tablets were in size of 9 mm. The core contained 24 mg of 13C3 caffeine (Eurisotop a Cambridge Isotope Laboratory Company, Cambridge, MA). The tablets were manufactured by direct compression (Nagema KP2 eccentric tablet press (VEB Kombinat Nagema, Dresden, Germany)) from the powder mixtures prepared according to the protocol and utilizing the same substances from the study of Tzakri et al. (Tzakri et al., 2023). Quality control of cores and pressed-coated tablets were performed and acceptance levels were reached (mean ± SD) (cores: breaking force (14 ± 4 N, n = 5), disintegration time (within 15 s, n = 3), weight (45 ± 2 mg, n = 20), height (2 mm, n = 10) and pressed-coated tablets: breaking force (87 ± 3 N, n = 4), disintegration time (within 20 s, n = 3), weight (265 ± 6 mg, n = 20), height (5 mm, n = 10), dissolution (300 mL SGFsp, 25 rpm, 37 °C) (> 90 % released within 5 min, n = 3)). Additionally, the pressed-coated tablets were tested in warm black tea (25 mL SGFsp, 240 mL black tea at 50 °C, 75 rpm, n = 3) to confirm the fast disintegration and caffeine release. The acceptance level was met. Pressed-coated tablets were also tested in warm water and cold water to confirm the homogenous behaviour and caffeine release (25 mL SGFsp, 240 mL water at 50 °C/8 °C, 75 rpm), n = 3 for every fluid). Fast disintegration and caffeine release were achieved in all fluids. Every tablet was packed separately in an aluminium bag (aluminium bags Ströbel GmbH (Langenzenn, Germany)). The details about the tablets’ preparation and quality control can be found in the publication Tzakri et al. (Tzakri et al., 2023).
Dorota Sarwinska, Mathilde Leyh, Constantin Foja, Theodora Tzakri, Philipp Schick, Felix Morof, Julius Krause, James Mann, Richard Barker, Mladen Vassilev Tzvetkov, Werner Weitschies, Michael Grimm, The effect of black tea and water temperature on the disintegration of gelatine and HPMC capsules, tested with the paddle device, GastroDuo and in vivo pharmacokinetics: Much ado about little, International Journal of Pharmaceutics: X,
Volume 9, 2025, 100342, ISSN 2590-1567, https://doi.org/10.1016/j.ijpx.2025.100342.
