The mechanics of gastrointestinal (GI) movement can have a significant impact on the release rate of the active pharmaceutical ingredient (API), which is especially pronounced in mechanically sensitive dosage forms such as hydrophilic matrix tablets. The latter are extended-release dosage forms that remain in the gastrointestinal tract (GIT) for a prolonged period of time and therefore enable a controlled release of API, which is why their behavior in fed state should also be anticipated. This is often the reason for the in vitro-in vivo correlation setup problems, so it is crucial to evaluate the parameters that may affect the dissolution process.
This master's thesis presents the (additive) effects of mechanics and food components on the dissolution of active pharmaceutical ingredients from hydrophilic matrix tablets. For this purpose, we produced two types of matrix tablets - tablets with higher (90SH 100 000SR) and lower (90SH 100SR) HPMC viscosity grade with paracetamol as a model substance. In order to get as close as possible to the in vivo fed state conditions, we optimized the conditions of the in vitro dissolution testing and selected suitable dissolution media such as simulated orange juice, Ensure Plus®, whole milk (3,5 %), 40 % ethanol, etc. Dissolution testing was performed on a paddle apparatus (USP2) and on a biorelevant dissolution apparatus - an advanced gastric simulator (AGS). The latter generates similar luminal pressures as those observed in vivo. The first part of the thesis evaluates the influence of the mechanics and hydrodynamics of the devices used, while the second part assesses the influence of the food components on the dissolution course. Tablet erosion was monitored to support the results and the properties of the gel layer were evaluated visually as well as with the help of a Texture analyser. It was shown that the pronounced mechanics in an AGS lead to greater tablet wear and in most cases accelerated the dissolution of the active ingredient relative to the USP2.
We set up Higuchi and Korsmeyer-Peppas models and our own model that helped us qualitatively evaluate the impact of hydrodynamics or mechanics. It was in line with other findings regarding the additive power of the influence of the mechanics and the dissolution medium on a change in the dissolution kinetics. The accepted theory of delayed dissolution in the presence of food was partly disproved and it was discovered that in fed state, the formulation with a higher HPMC viscosity grade is not necessarily more robust. From the point of view of safety we obtained interesting results in 40 % ethanol on the AGS, where the so-called ‘dose dumping’ effect occurred - most of the dose dissoluted in a relatively short time.
|
