Droplet microfluidic fabrication of dimpled poly(lactic acid)-poloxamer microparticles for tuneable depot...

The development of long-acting injectable (LAI) formulations with precise control over drug release and high batch-to-batch reproducibility remains a major challenge, primarily due to limited control over particle formation dynamics and internal microstructure. Here, we integrate droplet microfluidics with newly synthesized poly(lactic acid)-poloxamer-poly(lactic acid) (PLA_PLU_PLA) triblock copolymers (having 0.05 to 0.2 wt% PLU) to engineer drug-loaded microparticles (MPs) with controlled interfacial assembly and phase behaviour. This approach enabled the reproducible fabrication of highly monodisperse MPs (coefficient of variation for MPs' size was below 10%) with tuneable size and morphology. MPs with diameters ranging from 34.8 ± 0.9 to 44.4 ± 1.6 μm were produced, while systematic variation of PLU content enabled precise modulation of surface architecture, producing golf-ball-like dimples and reduced porosity at higher and lower PLU content, respectively. This transition suggests PLU-dependent modulation of interfacial tension and phase segregation during solvent extraction, governing surface characteristics. Enzymatic degradation studies revealed a non-linear dependence on composition, with 0.1 wt% PLU MPs exhibiting the slowest degradation (10.7 ± 1.5% weight loss at 20 days), indicating a balance between hydrophilicity-driven water uptake and reduced matrix accessibility. Using paliperidone palmitate as a model active pharmaceutical ingredient, MPs with intermediate PLU content showed the most prolonged release profile (∼ 42% over 14 days), with phenomenological release modelling suggesting a balance between diffusional transport and matrix erosion governed by composition-dependent characteristic. Drug loading and encapsulation efficiency (11.8-16.5% and 68.0-88.0%, respectively) were composition-dependent, reflecting altered API-copolymer partitioning. Collectively, these findings establish the use of droplet microfluidics combined with rational PLA/PLU triblock copolymer design as a powerful and versatile platform for engineering next-generation depot formulations with tuneable MPs' morphology, degradation, and drug release performance.