Formulation and Characterization of Nadolol Transdermal Delivery Using 3² Factorial Design: In Vitro and Ex Vivo Evaluation

The main objective of the research was to develop and optimize a transdermal drug delivery system (TDDS) for Nadolol, a non-selective β-blocker with limited oral bioavailability (~ 30%) due to hepatic first-pass metabolism. Nadolol has possess a favourable properties for transdermal delivery, such as a moderate lipophilicity (log P ~ 1.2), a relatively low molecular weight (309.4 g/mol), and a long elimination half-life, which render it a suitable candidate for sustained systemic delivery through the skin. Transdermal patches were formulated using the solvent casting method with varying concentrations of hydroxypropyl methylcellulose (HPMC K4M) and propylene glycol (PG). A 3²-factorial design was employed to optimize the chosen independent variables (X1: HPMC K4M concentration: X2: propylene glycol concentration) concerning the dependant variables (Y1: % cumulative drug release, Y2: tensile strength and Y3: % elongation). The prepared patches were evaluated for mechanical properties, moisture content, drug content uniformity, in vitro release, ex vivo permeation, and physicochemical compatibility using FTIR and DSC studies. The results confirmed that the drug was compatible with the selected excipients, and all patches demonstrated good flexibility, tensile strength, and sustained drug release over 12 h. Among all formulations, batch N7 (HPMC K4M 5%, propylene glycol 0.1 mL) showed the best performance, with a cumulative drug release of 97.79%, a flux value of 4.8990 mg/cm²/h, and desirable mechanical strength. Ex vivo studies using shed snake skin supported the in vitro release findings, with drug permeation reaching 89.81%. The release kinetics followed zero-order and Fickian diffusion. This study reveals Nadolol as a promising candidate for transdermal delivery and illustrates that factorial design-based optimization of an HPMC patch can yield a simple, scalable, and economical approach for sustained release and enhanced bioavailability. Although in vivo and long-term stability investigations remain necessary, the results provide a robust basis for subsequent preclinical research.