Towards a better understanding of the drug release mechanisms in PLGA microparticles

Poly (lactic-co-glycolic) acid (PLGA)-based microparticles represent an attractive choice to control drug release over periods ranging from a few days up to several months, while ensuring good biocompatibility and complete biodegradability. Different types of mass transport phenomena might be involved in the control of drug release from PLGA-microparticles, including for instance water diffusion, drug dissolution, drug diffusion, polymer degradation, autocatalysis and polymer swelling. The relative importance of these phenomena can strongly depend on the composition, size and preparation technique of the systems. However, generally ensembles of microparticles are studied, differing in size and behavior.In order to better understand the drug release mechanisms from PLGA microparticles, the behavior of single microparticles after exposure to the release medium was studied.On the one hand, the main objective of this work was to better understand the root causes for the (up to) 3 drug release phases observed with poly (lactic-co-glycolic acid) (PLGA) microparticles containing drug particles: The 1st release phase (“burst release”), 2nd release phase (with an “about constant release rate”) and 3rd release phase (which is again rapid and leads to complete drug exhaust). The behavior of single microparticles was monitored upon exposure to phosphate buffer pH 7.4, in particular with respect to their drug release and swelling behaviors. In this study, PLGA-based microparticles were prepared by simple emulsion solvent extraction/evaporation method. Diprophylline and caffeine were selected as a model drugs at 5% of drug loading. In all cases, the release medium was phosphate buffer pH 7.4. Particle size analysis, thermal analysis, morphology, swelling and polymer degradation were evaluated to better understand the observed phenomena. Importantly, each microparticle releases the drug “in its own way”, depending on the exact distribution of the tiny drug crystals within the system. During the burst release, drug crystals with direct surface access rapidly dissolve. During the 2nd release phase tiny drug crystals (often) located in surface near regions which undergo swelling, are released. During the 3rd release phase, the entire microparticle undergoes substantial swelling. This results in high quantities of water inside the system, which becomes “gel-like”. The drug crystals dissolve and dissolved drug molecules rather rapidly diffuse through the highly swollen polymer gel.On the other hand, the importance of the experimental conditions on the in vitro drug release measurements was evaluated. The key factors described in the literature such as size, and temperature that may alter the in vitro drug release profiles from PLGA microparticles were evaluated. PLGA-based microparticles were prepared by simple emulsion solvent extraction/evaporation method. Diprophylline was selected as a model drug at 5% of drug loading. The studies were carried out both from ensembles of microparticles (in vitro release kinetics, PLGA degradation kinetics, morphology of microparticles after exposure to the medium) and from single microparticles (in vitro release, swelling kinetics and wet mass). All studies were performed under different release conditions (37°C/80 rpm, 20°C/80 rpm, 4°C/0 rpm) in order to identify which mechanisms, control the release of diprophylline. The obtained results show that the experimental conditions can impact the release kinetics in a significant or negligible way. These differences are due to the complicity of the mechanisms involved in the release of drug from PLGA microparticles.