In the case of poorly soluble weakly basic active pharmaceutical ingredients with pH-dependent solubility, including dipyridamole (DIP), supersaturation and precipitation may occur during transit of the gastrointestinal tract due to a large change in solubility. In this master thesis, we used a flow-through model to simulate transit from stomach to small intestine. With different media combinations we mimicked in vivo pH variability of the stomach (different HCl concentrations) and the small intestine (different pH of diluted McIlvain buffers) in the fasted state to evaluate the effect of pH on DIP behaviour in the flow-through model.
The experiments in the flow-through model were divided to experiments with differently concentrated DIP solutions and experiments with manufactured DIP extended-release tablets. We also examined the changes in dissolved DIP in the flow-through model if no precipitation occurs. In the flow-through model we monitored in situ changes in dissolved DIP in the intestinal compartment with an UV-VIS fibre optic dip probe. For samples pumped out of the simulated intestinal compartment at time intervals, a double sampling system was used to determine the dissolved and overall pumped DIP fraction. To ensure the pH in the intestinal compartment did not change during the experiments despite of the inflow of the acid medium, an appropriate concentration of phosphate buffer, mimicking the bile pH value, was experimentally determined for each combination of HCl media and diluted McIlvaine buffer. Phosphate buffer was pumped into the intestinal compartment simultaneously and at the same rate as HCl.
DIP dissolution from tablets was also studied in USP II dissolution apparatus in media with different pH values. We concluded that due to DIP pH-dependent solubility a higher fraction of DIP is released in media with lower pH than in media with higher pH. In experiments with DIP solutions in the flow-through model, we found that HCl concentration has no significant effect on DIP behaviour, as a constant pH value is maintained in the intestinal compartment, and DIP is already dissolved at the beginning of the experiments. On the other hand, in experiments with tablets we found that HCl concentration affects DIP release rate from tablets, resulting in faster increasing in DIP concentrations in the intestinal compartment when more concentrated HCl is used. This is due to the higher DIP solubility in more concentrated acid, which allows faster DIP release from the tablets. We also concluded that the pH of the intestinal compartment medium has a great influence on DIP behaviour in experiments with solutions and tablets, as the equilibrium solubility of DIP and consequently the degree of supersaturation depend on the medium pH.
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