Effect of polymer source on in vitro drug release from PLGA microspheres.

Determination of the qualitative (Q1) sameness of poly (lactic-co-glycolic acid) (PLGA) polymers can be very challenging due to PLGA being a random copolymer with inherent heterogeneity. Performance variation of PLGA microsphere drug product as a result of altered PLGA characteristics has been recognized as a critical limiting factor in product development. It has been reported that PLGA characteristics and degradation profiles are sensitive to minor differences in the manufacturing and control processes. Accordingly, the objectives of the present research were: 1) to determine minor differences in the physicochemical properties (such as inherent viscosity/molecular weight (Mw), blockiness, and glass transition temperature (Tg)) and the hydrolytic degradation profiles of PLGA polymers from different sources; and 2) to investigate the impact of any differences determined in (1) on the physicochemical properties (Q3) and in vitro release of leuprolide acetate microspheres. PLGA polymers were purchased from three different sources with similar inherent viscosity/Mw, monomer (Lactide/Glycolide) ratio, and end group as per the manufacturers' certificate of analysis (COA). These PLGA polymers were evaluated using the same in-house methods and showed differences in their properties such as Mw and blockiness. Three compositionally equivalent leuprolide acetate microspheres were prepared via a solvent evaporation method using the three PLGA polymers from different sources. The prepared microspheres showed differences in their physicochemical properties (such as particle size, porosity and average pore diameter) as well as in their in vitro drug release characteristics (burst effect and release rate). These results indicate that polymer source related variations have the potential to significantly impact the Q3 sameness and therapeutic performance of long-acting PLGA microspheres. The fundamental understanding gained on polymer properties will make a critical contribution to the development of quality control strategies as well as to future regulatory guidance on the evaluation of such complex drug products.