Effect of Monomer Sequence Distribution on the Glass Transition Temperature of Poly(d,l-lactic-co-glycolic acid) (PLGA)

Poly(lactic-co-glycolic acid) (PLGA) has garnered considerable attention as a versatile platform for the delivery of active pharmaceutical ingredients (APIs). In the field of API delivery, the glass transition temperature (Tg) is widely recognized as a fundamental predictor of drug release kinetics from PLGA formulations. Despite making significant progress in understanding the qualitative trends and general effects of multiple molecular parameters on the glass transition properties of PLGA, accurately predicting the Tg value of a PLGA with a specific molecular weight and composition remains a challenge. One factor that has previously been overlooked is the contribution of statistical monomer sequence distribution to the Tg of PLGA. To address this research gap, we employed a novel Feed Rate-Controlled Polymerization (FRCP) technique to synthesize PLGA homopolymers with a comparable molecular weight and varying degrees of repeat unit (lactate (L, repeat unit A) and glycolate (G, repeat unit B)) sequence uniformity (uniform vs gradient PLGA) at different monomer compositions (lactide/glycolide (LA/GL) ratios). This allowed us to systematically investigate the effect of LA/GL sequence distribution on the glass transition properties of PLGA. We observed a significant negative deviation (<∼8 K) from the predictions of the Fox equation in the Tg vs copolymer composition plot, suggesting the presence of a repulsive interaction between the LA and GL monomers. The experimental Tg data and the measures of monomer sequence length obtained in our study exhibited quantitative agreement with the predictions of both the Johnston theory (based on the free volume concept) and the Barton theory (based on the configurational entropy concept). Based on our findings, we propose that by considering the copolymer composition and monomer dyad/triad distribution, it is possible to reasonably predict the Tg of a PLGA material using the alternating dyad or tetrad glass transition values (TgAB or TgAABB, respectively) obtained in our study, without the need for adjustable parameters.