Quality by Design‐Guided Transethosomal Gel of Donepezil Hydrochloride and Quercetin for Potential Alzheimer's Management: Stability‐Indicating Eco‐Compatible RP‐HPLC Method

ABSTRACT Alzheimer's disease requires innovative therapeutic strategies that not only alleviate symptoms but also protect neurons. Donepezil hydrochloride, a cholinesterase inhibitor, and quercetin, a potent antioxidant, were co‐formulated into a transethosomal gel to enhance brain delivery and therapeutic efficacy. To design and optimize a Quality by Design (QbD)‐based transethosomal gel containing Donepezil hydrochloride and Quercetin, and to establish a stability‐indicating, eco‐compatible RP‐HPLC method for their simultaneous estimation. Chromatographic separation was achieved on a C18 ODS column using an eco‐friendly mobile phase of acetonitrile–phosphate buffer (45:55, pH 3.4). Detection was performed at 240 nm, the isoabsorptive wavelength for both drugs. Method validation followed ICH guidelines, and forced degradation studies (acidic, basic, oxidative, thermal, photolytic) were conducted to achieve controlled degradation (5%–20%) while minimizing the use of hazardous solvents. The transethosomal gel was developed using QbD algorithms, optimizing critical parameters including particle size distribution (PDI), zeta potential, entrapment efficiency, and drug release profile. The optimized gel exhibited a vesicle size of 128.4 ± 2.1 nm, PDI of 0.135, zeta potential of +29.52 mV, and 89% and 85% entrapment efficiency of Quercetin and Donepezil HCl. Drug content exceeded 97% for both drugs, while cumulative drug release reached approximately 85%–95% over 10 h. The RP‐HPLC method demonstrated excellent linearity (R 2 > 0.995), recovery (98−102%), precision (%RSD < 2%), accuracy, robustness, and an Eco‐Scale score of 83.18, confirming excellent analytical greeness. Forced degradation studies confirmed its stability‐indicating capability. The study successfully integrates QbD‐driven formulation design with a validated eco‐friendly RP‐HPLC method, providing a robust platform for simultaneous drug delivery in Alzheimer's therapy. This work underscores the synergistic potential of advanced formulation strategies and sustainable analytical validation in translational pharmaceutical research.