HYDROPHILIC MATRICES FOR THE EXTENDED RELEASE OF A MODEL-DRUG EXHIBITING PH-DEPENDENT SOLUBILITY

After oral administration of basic drugs, the different pH values of the gastrointestinal tract can result in drastic changes in drug solubility, which can be very high at acidic pH values and dramatically low at neutral/basic pH, with consequent problems for the design of oral extended release formulations. In this paper, the preparation of an oral extended release formulation containing a basic drug is proposed, using dipyridamole as model. Three-component modified release granules capable of moderating the drastic dissolution behavior of dipyridamole were prepared by loading a swellable polymer (cross-linked sodium carboxymethylcellulose) with both the drug and an enteric polymer (cellulose acetate phthalate or cellulose acetate trimellitate). In vitro dissolution tests of modified release granules in USP gastric fluid showed a modulation of the high dissolution rate of dipyridamole at the acidic pH values, while in USP intestinal fluid a very marked improvement in drug dissolution was observed. Hydrophilic matrices containing the drug with the smoothed dissolution rate characteristics were prepared via mixing the granules with a gelling polymer (cellulose ether) and then tabletting the resulting mixture. In vitro release tests performed both at constant pH and with pH variation showed that the matrices are capable of providing extended drug release in both acidic and neutral/basic media.