Development and Characterisation of a Box-Behnken Optimised Polymeric Matrix Transdermal Patch of Aripiprazole: Ex Vivo Permeation, Stability and Skin Tolerability

Oral aripiprazole is limited by hepatic first-pass metabolism, CYP2D6-dependent exposure and the poor adherence that characterises long-term antipsychotic therapy. This study developed and characterised a polymeric matrix transdermal patch of aripiprazole by solvent casting. Preformulation work confirmed a lipophilic drug (log P 4.18 ± 0.09) that was compatible with all excipients, and a stability-indicating RP-HPLC method was validated (R² = 0.9999; recovery 99.6–100.2%; RSD ≤ 0.89%). Eight screening batches identified an HPMC K4M : ethyl cellulose N10 matrix as the most suitable base, and a 17-run, three-factor Box-Behnken design (polymer ratio, PEG 400 and oleic acid) was used for optimisation. The optimised patch (HPMC:EC 60:40, PEG 400 22% w/w, oleic acid 6% w/v) matched model predictions within 2.2% and showed drug content of 99.2 ± 0.4%, tensile strength of 4.08 ± 0.18 N/mm², folding endurance of 354 ± 18 and a surface pH of 6.28 ± 0.08. It released 73.4 ± 1.6% of the drug in 24 h by anomalous (non-Fickian) transport (Korsmeyer-Peppas n = 0.58) and, through excised rat skin, gave a steady-state flux of 17.8 ± 0.9 µg/cm²/h with an enhancement ratio of 1.93. Drug content remained at or above 95% after 6 months at 40 °C/75% RH and after 12 months at 25 °C/60% RH, although photostability testing showed that light protection is required. The patch was non-irritant in a reconstructed human epidermis model (viability 82.4 ± 4.1%) and in rabbits (primary irritation index 0.24). The findings support progression to in vivo pharmacokinetic evaluation.