(441b) Definition and Characterization of Blockiness in Poly(lactide-co-glycolide)

Poly(lactide-co-glycolide) (PLGA) is a biocompatible and biodegradable copolymer that is used as an excipient in some long-acting drug formulations. PLGA degradation and drug release can be tuned using the molecular weight, lactide:glycolide composition, and end-group. However, other properties including processing conditions, implant morphology, and crucially lactic/glycolic repeat unit ordering along the backbone of the copolymer have also been shown to affect degradation and drug release rates for PLGA implants. PLGA is utilized as an excipient in over 20 FDA-approved long-acting drug implants, but no generic versions of these products have been approved despite the expiration of several patents, partially owing to difficulties in proving equivalence. The measurement of PLGA blockiness has proven especially difficult, with several methods being proposed and no consensus on a standardized method. Most of the current methods take advantage of the sensitivity of chemical shift in the ¹³C NMR spectrum to neighboring repeat units, particularly the glycolyl carbonyl peak which is usually understood to represent GL and GG dyads. However, the effects of solvent choice, acquisition parameters, and neighboring lactyl unit stereochemistry on the glycolyl carbonyl peak remain largely unaccounted for. We propose a new method for measuring PLGA blockiness which depends instead on the glycolyl methylene peak in the ¹³C NMR spectrum. The methylene peak appears to be sensitive to the tetrad sequences on a 500 MHz NMR spectrometer (125 MHz for ¹³C), enabling more detailed sequence characterization compared to only GG/GL dyads. The effects of lactide stereochemistry are also minimized compared to the carbonyl peak. Until now, these advantages have not been used for sequence measurement due to the apparent complexity of the methylene peak and difficulty in assigning each of the peaks in the methylene region to sequence motifs. We developed a stochastic kinetic model of lactide/glycolide copolymerization which we compared to experimental deconvolutions of the methylene region to assign each peak to a G-centered tetrad (XGXX). We also define a blockiness parameter based on those assignments that can be calculated from experimental data. More careful consideration of PLGA sequence and the methods which are used to measure it will enable more complete characterization of existing PLGA’s and may even enable the use of sequence variation as a tunable property for commercially-produced PLGA.