With poorly soluble, weakly basic active pharmaceutical ingredients, which have a pH-dependent solubility, supersaturation and precipitation may occur during transit of the gastrointestinal tract due to a large change in solubility. Dipyridamole is one of them. In this master's thesis, we have reviewed the in vitro models which were used to study the precipitation of dipyridamole and investigated the effect of different hydrodynamic forces on the precipitation of dipyridamole from its supersaturated solution in three different in vitro systems.
By reviewing the in vitro models used to monitor dipyridamole precipitation in literature, we have identified the key parameters affecting dipyridamole precipitation and used them to design the experimental work. The key parameters were the choice of medium, the choice of dosage form, the choice of a suitable in vitro model and the duration of the experiments. We found that very different in vitro models were used to study dipyridamole precipitation, making it difficult to compare supersaturation times and maximum dissolved dipyridamole concentrations between models.
To investigate the effect of different hydrodynamic forces on dipyridamole precipitation, a solution of dipyridamole in 0,01 M HCl was prepared and added to a medium representing the fasted state of the small intestine to initiate the precipitation process. The experiments were carried out in a USP II dissolution system with conventional paddles and a smaller volume of medium, in a USP II dissolution system with mini paddles and narrow tall vessels and in a beaker system where the dispersion was stirred using a large and a small magnet. In all three in vitro systems, two stirring speeds were used. In the beaker system, glass beads were added in some experiments to provide additional mechanical stress. The variation of dissolved dipyridamole concentrations with time was monitored in situ with a fiber optic dip probe. The greatest differences in dipyridamole precipitation rates occurred in the beaker system when glass beads were present than when they were absent. Smaller differences in the precipitation rate of dipyridamole, as a result of different stirring speeds, occurred in USP II dissolution system with conventional paddles and a smaller volume of medium and in the beaker system where no glass beads were present. In USP II dissolution system with mini paddles and narrow tall vessels, the effect of stirring on dipyridamole precipitation was negligible, which is consisted with literature data.
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