End-group-selective size-exclusion chromatography-mass spectrometry of poly(lactic acid) and poly(lactide-co-glycolide) polymers.

End-group-selective size-exclusion chromatography (esSEC) coupled with mass spectrometry (MS) is presented as an analytical approach for the separation and characterization of acid-terminated and non-acid-terminated poly(lactic acid) (PLA) and poly(lactide-co-glycolide) (PLGA). The method uses a gradient normal-phase liquid chromatography system with basic (triethylamine) and acidic (formic acid) additives in ethyl acetate-based mobile phases, enabling selective retention of acid-terminated polymers, while non-acid-terminated species elute according to hydrodynamic volume (i.e., their effective size in solution). Following their release from the stationary phase, the acid-terminated polymers also undergo separation according to hydrodynamic volume. Gradient steepness strongly influenced the elution behavior of acid-terminated polymers. Shallow gradients resulted in broader elution profiles reflecting prolonged adsorption-desorption, whereas steeper gradients produced sharper, more symmetrical peaks. The method can be directly coupled to MS, enabling molecular-level characterization of end-group structures and chemical composition across the chromatographic separation. The proposed esSEC-MS method provides a novel strategy for end-group-resolved polymer analysis. Its applicability is demonstrated by monitoring the formation of cyclic structures by intramolecular transesterification and the degradation of an ester-terminated PLGA copolymer over time.