**Background:** Curcumin, the main polyphenolic component of turmeric (Curcuma longa), has demonstrated therapeutic efficacy in arthritis, liver diseases, neurodegenerative diseases, various cancers, obesity, wound-healing, anti-inflammatory treatments, and as an antibacterial, antioxidant, antispasmodic, and anticoagulant agent. Despite these benefits, clinical application is severely limited by curcumin's high hydrophobicity (solubility of 0.125 mg/L in water), rapid metabolism, and oxidative instability. Nanoliposomes have emerged as promising delivery vehicles to overcome these limitations, but existing manufacturing methods suffer from being batch-based, energy-intensive, requiring toxic solvents, and lacking scalability. The authors previously developed a novel 'simil-microfluidic' technology (patent WO2019049186) that enables continuous, room-temperature production of nanoliposomes without toxic solvents or specialized micro-fabricated devices.
**Methods:** Liposomal curcumin suspensions were produced using the simil-microfluidic apparatus with a coaxial insertion system. The hydration solution (deionized water) and lipid ethanol solution (containing L-α-Phosphatidylcholine from soybean, cholesterol, and curcumin) were pumped at volumetric flow rates of 45 mL/min and 4.5 mL/min respectively (10:1 ratio), yielding approximately 3 L/hour of liposomal suspension. Seven production batches were prepared with varying curcumin concentrations: theoretical curcumin concentrations in ethanol ranged from 6.99 mg/mL (batch 1) down to 0.49 mg/mL (batch 6). Batch 7 used half the lipid amount with a curcumin concentration of 0.71 mg/mL. A two-step separation protocol was employed: syringe filtration (450 nm pore size) to remove coarse aggregates, followed by tangential flow filtration (TFF) to separate loaded vesicles from the hydroalcoholic suspension. Characterization included dynamic light scattering (DLS) for size and polydispersity index, UV-VIS spectrophotometry at 426 nm for curcumin quantification, optical microscopy, and transmission electron microscopy (TEM). Stability was assessed after one month storage at 4°C protected from light. Statistical analysis used Student's T-test and one-way ANOVA with significance at p < 0.05.
**Key Results:** The Reynolds number of 240 confirmed laminar flow conditions, with mixing governed primarily by diffusion mechanisms. For batch 1 (highest curcumin concentration), encapsulation efficiency was only 11.12% with an effective load of 1.23%, and extensive curcumin aggregate formation was observed. As curcumin concentration decreased from batch 1 to batch 6, syringe separation efficiency (reflecting curcumin retained as aggregates) decreased from 11.13% to 89.74%, indicating progressively less aggregate formation. The optimal results were achieved with production batch 5, showing encapsulation efficiency of 89.47% and effective load of 1.15%, and batch 6 with encapsulation efficiency of 89.71%. Effective load values remained roughly constant around 1.3% across batches, suggesting a critical load-limit with respect to lipid composition. DLS analysis showed that the modal value of the intensity probability distribution function (x_mod,6), which reflects large particles or aggregates, decreased significantly after syringe filtration for batches 1-4, while for batches 5 and 6, x_mod,6 values were already low before filtration, confirming absence of aggregates. The numerical mean size (x_1,0) consistently fell between 100-250 nm across all batches. TEM imaging confirmed spherical nanosized vesicles. Statistical analysis showed that CUR/PC ratio significantly affected Z-Average (p = 0.005) and x_mod,6 (p = 0.002), but not x_1,0 (p = 0.086). Batch 7 (reduced lipid content) showed markedly worse performance with encapsulation efficiency of only 29.14% and effective load of 0.70%, with aggregate formation confirmed by optical microscopy. Stability studies showed that filtered samples maintained size and curcumin retention under refrigerated conditions for one month.
**Clinical Implications:** This study demonstrates that the simil-microfluidic technology can produce curcumin-loaded nanoliposomes with encapsulation efficiencies approaching 90% and loads exceeding 1% at room temperature with minimal energy requirements and at industrially relevant production rates (3 L/hour). The identification of a critical curcumin concentration threshold that prevents aggregate formation is crucial for manufacturing consistent, high-quality nanoliposomal curcumin products. These findings support the feasibility of scalable production of nanoliposomal curcumin, which has shown promise in clinical applications including cancer therapy, anti-inflammatory treatments, and neurodegenerative disease management. The technology addresses key manufacturing barriers that have limited the translation of curcumin's therapeutic potential from bench to bedside.