Influence of polymerisation conditions on the kinetics of poly(lactic-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) triblock synthesis and the occurrence of transesterification side reactions

Abstract

Poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) (PEG-PLGA) block copolymers and their thermoresponsive hydrogels have been widely studied as injectable depots for the sustained release of therapeutics. The thermogelling temperatures of PEG-PLGA copolymer solutions and the properties of their corresponding hydrogels are highly sensitive to the polymer microstructure. Often, it can be difficult to precisely control the microstructure because of transesterification side reactions that occur during ring-opening polymerisation (ROP) of lactide (L) and glycolide (G) monomers under various conditions. Therefore, we undertook a detailed study to understand how different reaction conditions influenced the reaction kinetics, monomer sequence and side reactions for the synthesis of a PLGA-PEG-PLGA triblock copolymer. ROP was conducted under thermal control (100, 110 and 120 °C) or in the presence of the catalysts tin(II) 2-ethylhexanoate (Sn(Oct)₂) and tin(II) trifluoromethanesulfonate (Sn(OTf)₂) at various catalyst loadings. The reactions were monitored via proton nuclear magnetic resonance (¹H NMR) spectroscopy, gel permeation chromatography (GPC) and matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI ToF MS). While ROP proceeded faster with catalysts than the uncatalysed reaction at an equivalent temperature, the onset of side reactions typically occurred at much lower monomer conversions and to a greater extent, resulting in a plateau in the molecular weight and broadening of the molecular weight distribution. For Sn(Oct)₂ catalysed ROP, an increase in the catalyst loading had negligible effect on the occurrence or extent of side reactions, but led to a surprising increase in the rate of polymerisation of L relative to G. Sn(OTf)₂ catalysed ROP resulted in significant side reactions from the start of the polymerisation. These results provide insights into the influence of polymerisation conditions on the microstructure of PLGA-PEG-PLGA triblock copolymers that may prove useful for their improved and controlled synthesis.