Dissolution behavior of diclofenac sodium (DS) from wax matrix granules (WMGs) prepared using a twin-screw compounding extruder is closely related to swelling ability and solubility of the rate-controlling agent employed. A swellable and soluble (hydroxypropyl)-cellulose (HPC-SL) generates both an expansion of pores inside WMGs and a structural change observed as cracking on the surface of WMGs. These changes are confirmed by mercury porosimetry. Release of DS was increased with an increase in the amount of HPC-SL in WMGs, but only 35% of DS was released from WMGs containing 73% (w/w) NaCl at the 24 h point of the dissolution. Further, no cracking was observed on the surface of NaCl-containing WMGs. A linear relationship between mean dissolution time (MDT) of DS for WMGs containing different types of HPC (HPC-SL, -M, and -H) and swelling abilities suggests that release of DS could be directly controlled by swelling of HPCs. In addition to this result, an application of the exponential model (Mt/M infinity = kt(n)) introduced by Ritger and Peppas (J. Controlled Release 1987, 5, 23-36) to DS release indicates that case II release plays a critical role in HPC-SL-containing WMGs and Fickian release is predominant in NaCl-containing WMGs since the values of n of WMGs containing 73% (w/w) NaCl and 40% (w/w) HPC-SL are 0.41 and 0.71, respectively. These results suggest that proper selection of rate-controlling agents based on their physicochemical properties (such as swelling ability and solubility) is important in designing WMGs with desired dissolution profiles.

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The in vivo performance of wax matrix granules (WMGs) prepared by a twin-screw compounding extruder was evaluated in fasted beagle dogs. In vitro dissolution behavior of the model drug, diclofenac sodium (DS), from WMGs was strongly influenced by pH in a dissolution medium due to its solubility (DS is soluble in pH 6.8 and insoluble in pH 1.2 and 4.0) and was independent of paddle rotation rate (50, 100, and 200 rpm) of the dissolution apparatus. Pharmacokinetics parameters such as mean residence time (MRT) showed a sustained action of WMGs in beagle dogs; however, the transit time of WMGs in the small intestine is found to control total drug absorption. Furthermore, the values of the area under the curve (AUC) of the plasma concentration-time curve and the maximum concentration Cmax significantly decreased with decreases in hydroxypropylcellulose (HPC) content in WMGs. Good correlation between one in vitro dissolution parameter (mean dissolution time, MDT) and two in vivo parameters (AUC12 and MRT) suggested that it would be possible to design WMGs with a desired in vivo performance by controlling HPC content.

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