Development of a Multiple Unit Pellet Formulation for a Weakly Basic Drug

SAG/ZK [3-(5-Chloro-2-[2-[(2R)-4-(4-fluorobenzyl)-2-methylpiperazin-1-yl]-2-oxoethoxy]phenyl)uronium hydrogen sulfate], a potent candidate for the oral treatment of inflammatory diseases, demonstrated pH-dependent solubility. Drug release from conventional pellet formulations decreased with increasing pH values of the dissolution medium. The aim of this study was to overcome this problem and to achieve pH-independent drug release. Extended release pellets were prepared by extrusion/spheronization followed by film coating with an aqueous polyvinylacetate/polyvinylpyrrolidone dispersion. To overcome the problem of pH-dependent drug release organic acids such as fumaric, tartaric, and adipic acid were incorporated into the core pellets. X-ray diffraction studies were done in order to investigate potential recrystallization and formation of different salts of SAG/ZK. The addition of fumaric acid was found to lower the pH values within the core pellets during the release of SAG/ZK in phosphate buffer pH 6.8. Therefore, increased release rates at higher pH values were observed thus leading to pH-independent drug release. In contrast, drug release remained pH-dependent for pellets containing tartaric and adipic acid, which can be explained with the lower acidic strength and higher aqueous solubility of these acids. X-ray diffraction studies showed no recrystallization and formation of salts of active ingredient and organic acid.