AbstractRelease of triamterene from 150–300 gm poly(DL-lactide-co-glycolide) (PLGA) microspheres was investigated in vitro as a function of lactic acid/glycolic acid (LA/GA) copolymer ratio and drug loading both with free microspheres and with microspheres embedded in a silicone matrix. Biphasic release consisting of diffusion controlled release followed by erosion controlled release corresponding to polymer degradation was observed in all samples. Drug release from PLGA 50:50 copolymer microspheres was three times faster than the release from PLGA 75:25 microspheres for the higher drug loading (20 wt%) and slightly faster for the lower drug loading (10 wt%). Release rates from spheres containing the higher drug loading were approximately one order of magnitude faster than release from spheres containing the lower drug loading for the same PLGA copolymer. The same qualitative results were observed for the spheres embedded in silicone matrices; however, the overall release was much slower. The results demonstrate that release behavior may be altered by changing LA/GA copolymer ratio, drug loading, and microsphere environment to obtain the desired release characteristics.