Using a Novel Multicompartment Dissolution System to Predict the Effect of Gastric pH on the Oral Absorption of Weak Bases with Poor Intrinsic Solubility
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Abstract
A novel multicompartment dissolution system was developed by modifying a conventional
six-vessel United States Pharmacopoeia dissolution system to study the dissolution
and possible precipitation of poorly soluble weak bases after oral administration.
The modified system includes a "gastric" compartment, an "intestinal" compartment,
an "absorption" compartment, and a reservoir to simulate the dissolution and absorption
in the gastrointestinal tract. Dissolution profiles of 50-mg dipyridamole (pK(a) 6.0,
12.5) tablet (2 * 25 mg Persantine tablets), 25- and 50-mg cinnarizine (pK(a) 1.95,
7.5) powders, which are poorly soluble weak bases, were generated in the system using
dissolution medium with different pHs in the "gastric" compartment. The in vitro dissolution
results were compared with the in vivo oral exposure data in humans. For both dipyridamole
and cinnarizine, the in vitro dissolution using the multicompartment system was able
to predict the pH effect on oral exposure. The results from the multicompartment system
are more closely correlated with the in vivo data, compared with that from the conventional
dissolution test. The system showed that although both dipyridamole and cinnarizine
completely dissolved in the gastric compartment at lower pH, approximately 36% (at
25-mg dose) and 40% (at 50-mg dose) of cinnarizine precipitated in the "intestinal"
compartment whereas the precipitation of dipyridamole was <10% of the initial dose.
The difference in the amount "absorbed" between these two compounds in vitro is therefore
primarily attributed to the precipitation potential, although no in vivo data are
available to confirm this result. The difference in the amount precipitated may be
explained by the lower solubility and consequently higher degree of supersaturation
of cinnarizine in the "intestinal" compartment.