Milling-Induced Chitosan-HPMC Microstructural Organisation Determines the Stability Window of Concentrated Azelaic Acid Nanosuspensions.

Objectives

The physical stability of concentrated azelaic acid nanosuspensions cannot be predicted solely from interfacial stabilisation but reflects the interplay between particle size-dependent thermodynamic driving forces, polymer-mediated rheological structuring and the resulting bulk microstructural organisation. This study employed an A-optimal design of experiments (18 runs) to investigate formulation-process relationships in concentrated azelaic acid nanosuspensions (10-20% w/w) stabilised with a dual HPMC-chitosan system.

Methods

Particle size, ζ-potential, rheological behaviour, solid-state properties and in vitro permeation across Strat-M® membranes were evaluated, and formulation-process relationships were analysed using multivariate modelling and logistic regression.

Results

Particle size (342-1118 nm; R2 = 0.97) was primarily governed by the applied milling regime. Logistic regression demonstrated a size-dependent probability of crystal growth, with the estimated particle-size transition point (predicted probability = 0.5) shifting from approximately 424 nm after preparation to 594 nm following accelerated storage at 40 °C. CHI concentration controlled ζ-potential (+18.5 to +47.9 mV), although ζ-potential alone did not adequately explain the observed storage stability. Where measurable, zero-shear viscosity (68-45,462 mPa·s) reflected substantial differences in low-shear rheological structuring, while formulations containing higher HPMC concentrations generally exhibited improved stability, consistent with polymer-mediated kinetic constraints on crystal growth. In vitro permeation studies using Strat-M® membranes demonstrated permeation behaviour consistent with structured diffusion-controlled systems, exhibiting lower flux but more uniform permeation profiles than the reference formulation under the applied experimental conditions.

Conclusions

Integration of multivariate modelling with rheological, solid-state and permeation characterisation provided an integrated understanding of the formulation-process relationships governing the short-term physical stability and comparative in vitro transport behaviour of concentrated dermal AZA nanosuspensions.