Diagnostic ultrasound has been shown to be an effective method for the noninvasive characterization of in situ forming implant behavior both in vivo and in vitro through the evaluation of the echogenic signal that forms as a consequence of the polymer phase transition from liquid to solid. The kinetics of this phase transition have a direct effect on drug release and can be altered through factors that change the mass transfer events of the solvent and aqueous environment, including properties of the entrapped active agent. This study examined the effect of payload properties on implant phase inversion, swelling, drug release, and polymer degradation. Poly(DL-lactide-co-gylcolide) implants were loaded with either: sodium fluorescein, bovine serum albumin (BSA), doxorubicin (Dox), or 1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI). Fluorescein and Dox were released at near equivalent rates throughout the diffusion phase of release but due to differing drug-matrix interactions, Dox-loaded implants released a lower mass of drug during the degradation phase of release. DiI was not readily released, and due to increased depot hydrophobicity, resulted in significantly lower swelling than the other formulations. The initial echogenicity was higher in Dox-loaded implants than those loaded with fluorescein, but after the initial precipitation, phase inversion and drug release occurred at near equivalent rates for both Dox and fluorescein-loaded implants. Nonlinear mathematical fitting was used to correlate drug release and phase inversion, providing a noninvasive method for evaluating implant release (R(2)>0.97 for Dox, BSA, and fluorescein; DiI had a correlation coefficient of 0.56).