Comparative Analysis of Sonication, Microfluidics, and High-Turbulence Microreactors for the Fabrication and Scaling-Up of Diclofenac-Loaded Liposomes

<b>Background</b>: Liposomes are attractive topical carriers, yet translating laboratory fabrication to scalable, well-controlled processes remains challenging. <b>Objectives</b>: We compared three manufacturing methods for diclofenac-loaded liposomes: probe sonication, microfluidic mixing, and a high-turbulence microreactor, under a Quality-by-Design framework. <b>Methods</b>: Differential scanning calorimetry (DSC) was used to define a processing-relevant liquid-crystalline temperature window for the lipid excipients. For sonication scale-up, a Plackett-Burman screening design identified key process factors and supported an energy-density (W·s·L^-1) control approach. For microfluidics, the effects of flow-rate ratio (FRR) and total flow rate (TFR) were mapped and optimized using a desirability function. Microreactor trials were performed at elevated throughput. Residual ethanol during post-processing was monitored at-line by Raman spectroscopy calibrated against gas chromatography (GC). Particle size and dispersity were measured by DLS and morphology assessed by cryo-TEM. <b>Results</b>: DSC supported a 70-85 °C processing window. Sonication scale-up using an energy-density target (~11,000 W·s·L^-1) reproduced lab-scale quality at 8 L (Z-average ~87-92 nm; PDI 0.16-0.23; %EE 86-94%). Microfluidics optimization selected FRR 3:1/TFR 4 mL·min^-1, yielding ~64 nm liposomes with PDI ~0.13 and %EE ~93%. The microreactor achieved ~50 nm liposomes with %EE ~95% at 50 mL·min^-1. Cryo-TEM corroborated size trends and showed no evident aggregates. <b>Conclusions</b>: All three routes met topical CQAs (~50-100 nm; PDI ≤ 0.30; high %EE). Method selection should be guided by target size/dispersity and operational constraints: sonication enables energy-based scale-up, microfluidics offers precise size control, and microreactors provide higher throughput.