Acne vulgaris is a common, multifactorial, inflammatory skin disease affecting the pilosebaceous unit. Topical therapy is the first choice in the treatment of mild to moderate acne, and azelaic acid (AZA) is one of the most commonly used drugs. The aim of this study was to evaluate the safety and efficacy of a low-dose azelaic acid nanocrystal (AZA-NC) hydrogel in the treatment of mild to moderate facial acne. The study was designed as a double-blind, randomized controlled trial. Patients were randomized to treatment with AZA-NC hydrogel, 10%, or AZA cream, 20%, administered in quantities of approximately 1 g twice daily for 8 weeks. Efficacy of therapy was measured by the number of lesions and safety by the frequency and severity of adverse events. At week 8, the success rate of treatment with AZA-NC hydrogel, 10%, was 36.51% (p < 0.001) versus 30.37% (p < 0.001) with AZA cream. At week 8, treatment with AZA-NC hydrogel, 10%, resulted in a significant reduction in total inflammatory lesions from baseline of 39.15% (p < 0.001) versus 33.76% (p < 0.001) with AZA cream, and a reduction in non-inflammatory lesions from baseline of 34.58% (p < 0.001) versus 27.96% (p < 0.001) with AZA cream, respectively. The adverse event rate was low and mostly mild.

Background/Objectives: This study investigates the stabilisation mechanisms of azelaic acid nanosuspensions (AZA-NS) prepared by wet media milling (WMM) using hydroxypropyl methylcellulose (HPMC) and chitosan as stabilisers. The aim was to elucidate the physical interactions relevant for stabilisation and to evaluate the effectiveness of a dual stabiliser approach to improve AZA-NS stability. Methods: AZA-NS were characterised using Fourier transform infrared spectroscopy (FTIR) to evaluate the chemical interactions, differential scanning calorimetry (DSC) for thermal properties, atomic force microscopy (AFM) to analyse the adsorption of the stabiliser on the AZA surface and X-ray diffraction (XRD) to evaluate the crystallinity. Contact angle and immersion studies were performed to evaluate wettability, and alternative stabilisers were tested for comparison. Results: Highly concentrated AZA-NS (up to 20% drug loading) were successfully produced with particle sizes between 326.8 and 541.2 nm, which are in the optimal range for follicular drug delivery. FTIR confirmed stabilisation by adsorption and not by chemical interaction. DSC revealed a melting point depression, indicating a partial disorder of the crystal lattice. AFM imaging showed different adsorption patterns for HPMC and chitosan, suggesting better surface coverage compared to alternative stabilisers. XRD confirmed the retention of the AZA crystalline form after milling. Contact angle and immersion studies showed improved wettability due to the synergistic effects of HPMC and chitosan. Alternative stabilisers showed suboptimal performance, highlighting the superior stabilising potential of the HPMC–chitosan combination. Conclusions: This study provides important insights into the dual stabilisation mechanisms and highlights the importance of combining steric and electrostatic stabilisers for the formulation of stable nanosuspensions of medium soluble drugs such as AZA. These results support the development of optimised nanosuspensions with increased stability and improved pharmaceutical applicability.

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.