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• Successful and controlled syntheses of star-shaped poly(ethylene oxide)- block -poly(lactic-co-glycolic) acid (PEG-PLGA) with two different molar masses and up to three blockiness values per molar mass, suitable for in-situ forming depot systems. • Characterization and distinction between star-shaped PEG-PLGA with same molar masses but different blockiness values by quantitative carbon-13 nuclear magnetic resonance for challenging-to-characterize PEG-PLGA copolymers. • Blockiness values from 0.33 to 1.10 demonstrated an impact on the degradation and in particular postulates about the polymer matrix composition over time. The thorough characterization of complex polymeric excipients is essential to ensure the quality, safety, and efficacy of pharmaceutical formulations, as well as to enhance reproducibility in the production of generics. Within this context, our study focused on understanding the impact of blockiness on the degradation of star-shaped poly(ethylene glycol)- block -poly(lactic- co -glycolic acid) (PEG-PLGA) copolymers. These copolymers, with varied monomer sequence distributions and molar masses, were synthesized through bulk ring-opening polymerizations. Different blockiness values were achieved by employing either tin- or zinc-based catalysts, or by varying the monomer addition sequences. The resulting products were characterized using quantitative carbon-13 nuclear magnetic resonance to evaluate monomer alternation. Intended for use as excipients in in situ forming depots, these amphiphilic copolymers underwent a 3-month degradation study in PBS at 37 °C. The study revealed that depot erosion, measured by weight loss, was appreciably influenced by the blockiness value for star-shaped PEG-PLGAs with a molar mass of approximately 25 kg mol −1 , while a less significant impact was observed for products with smaller PLGA segments. On a molecular level, we demonstrated that, for a given molar mass, the monomer alternation within the copolyester segments of star-shaped PEG-PLGAs significantly affects the chemical composition of the degraded depots. Specifically, structures with high blockiness values displayed an increased formation of PLA homopolymers during degradation, which ultimately slowed down the erosion process.