Development and Statistical Optimization of Ascorbic Acid–Phosphatidylcholine Complexes for Enhanced Topical Delivery

Abstract

Background: Ascorbic acid is a hydrophilic antioxidant and melanogenesis-modulating agent whose topical performance is limited by instability and restricted partitioning through the stratum corneum. Objective: To develop phosphatidylcholine (PC)-based ascorbic acid complexes by thin-film hydration and optimize formulation/process variables using a four-factor Box–Behnken design. Methods: Drug:PC ratio, film-formation temperature, hydration temperature and hydration time were varied across 27 runs. Entrapment efficiency (%EE) was the principal response and was analyzed by reduced quadratic response-surface modelling and ANOVA. Results: Preliminary drug-loaded batches produced 32.15 ± 2.41% to 48.63 ± 3.52% EE. Across the optimization runs, %EE ranged from 36.28 ± 2.76% to 52.14 ± 3.84%. The model was significant (F=15.20, p<0.0001), with R²=0.8711, adjusted R²=0.8137, predicted R²=0.7099 and adequate precision=11.642. Numerical optimization predicted 52.52% EE; experimental validation yielded 53.6 ± 0.4%, with checkpoint prediction errors below 4%. Conclusion: The optimized PC system provided reproducible entrapment of ascorbic acid and demonstrated a statistically robust design space suitable for further topical formulation development.