Design, optimization, and characterization of an ivermectin-loaded nanoemulsion using a quality by design approach

Abstract

Ivermectin is a BCS Class II drug with aqueous solubility below 0.005 mg/mL and log P of 5.83. Its topical delivery from conventional cream-based systems remains limited due to poor dermal bioavailability. The present study was carried out to develop and optimize an ivermectin-loaded topical nanoemulsion using a Quality by Design approach. QTPP definition, FMEA-based risk assessment, and 3² full factorial design were the key steps followed. From solubility screening, oleic acid, Tween 80, and propylene glycol were found to be the most suitable excipients. Among five Smix ratios evaluated through pseudoternary phase diagrams, Smix 4:1 showed the widest nanoemulsion existence zone and was hence selected. FMEA identified oil concentration (RPN = 448) and Smix concentration (RPN = 392) as critical process parameters. These were investigated across nine factorial batches and significant linear models were confirmed for all three responses. Checkpoint validation identified F10 as the optimized formulation at oil 5.83% and Smix 53.83%. It showed droplet size of 57.18 ± 2.36 nm, PDI of 0.251, transmittance of 99.8%, viscosity of 135.4 cps, and 1.43-fold higher drug release at 1 h in comparison to plain drug solution. Thermodynamic stability testing confirmed the physical robustness of the developed nanoemulsion under all stress conditions evaluated. The systematic QbD-driven optimization successfully established a robust design space for the formulation. Collectively, these findings demonstrated the potential of the optimized nanoemulsion as a promising platform for enhancing topical dermal delivery of ivermectin.