{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T08:20:39Z","timestamp":1787818839685,"version":"build-2784847793"},"reference-count":50,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Strengthening the scientific research and innovation capacities of the Faculty of Pharmacy and Biochemistry, University of Zagreb","award":["KK.01.1.1.02.0021"],"award-info":[{"award-number":["KK.01.1.1.02.0021"]}]},{"award":["KK.01.1.1.02.0021"],"award-info":[{"award-number":["KK.01.1.1.02.0021"]}],"id":[{"id":"https:\/\/ror.org\/00mv6sv71","id-type":"ROR","asserted-by":"publisher"}]},{"name":"European Regional Development Fund, Operational Program Competitiveness and Cohesion"},{"id":[{"id":"https:\/\/ror.org\/01rkhv978","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>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\u2013process relationships in concentrated azelaic acid nanosuspensions (10\u201320% w\/w) stabilised with a dual HPMC\u2013chitosan system. Methods: Particle size, \u03b6-potential, rheological behaviour, solid-state properties and in vitro permeation across Strat-M\u00ae membranes were evaluated, and formulation\u2013process relationships were analysed using multivariate modelling and logistic regression. Results: Particle size (342\u20131118 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 \u00b0C. CHI concentration controlled \u03b6-potential (+18.5 to +47.9 mV), although \u03b6-potential alone did not adequately explain the observed storage stability. Where measurable, zero-shear viscosity (68\u201345,462 mPa\u00b7s) 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\u00ae 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\u2013process relationships governing the short-term physical stability and comparative in vitro transport behaviour of concentrated dermal AZA nanosuspensions.<\/jats:p>","DOI":"10.3390\/pharmaceutics18091071","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T08:02:27Z","timestamp":1787817747000},"page":"1071","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Milling-Induced Chitosan\u2013HPMC Microstructural Organisation Determines the Stability Window of Concentrated Azelaic Acid Nanosuspensions"],"prefix":"10.3390","volume":"18","author":[{"given":"Sandra","family":"Mio\u010di\u0107","sequence":"first","affiliation":[{"name":"PLIVA Croatia Ltd., 10000 Zagreb, Croatia"},{"name":"University of Zagreb Faculty of Pharmacy and Biochemistry, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Ra\u0161i\u0107","sequence":"additional","affiliation":[{"name":"PLIVA Croatia Ltd., 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelena","family":"Tori\u0107","sequence":"additional","affiliation":[{"name":"PLIVA Croatia Ltd., 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9785-3741","authenticated-orcid":false,"given":"Michela","family":"Abrami","sequence":"additional","affiliation":[{"name":"Department of Engineering and Architecture, University of Trieste, I-34127 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7883-1769","authenticated-orcid":false,"given":"Kristina","family":"Ferderber","sequence":"additional","affiliation":[{"name":"PLIVA Croatia Ltd., 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1227-9024","authenticated-orcid":false,"given":"Biserka","family":"Cetina-\u010ci\u017emek","sequence":"additional","affiliation":[{"name":"PLIVA Croatia Ltd., 10000 Zagreb, Croatia"},{"name":"University of Zagreb Faculty of Pharmacy and Biochemistry, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3532-3200","authenticated-orcid":false,"given":"Mario","family":"Grassi","sequence":"additional","affiliation":[{"name":"Department of Engineering and Architecture, University of Trieste, I-34127 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2338-9739","authenticated-orcid":false,"given":"Jelena","family":"Filipovi\u0107-Gr\u010di\u0107","sequence":"additional","affiliation":[{"name":"University of Zagreb Faculty of Pharmacy and Biochemistry, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"ref_1","first-page":"1","article-title":"State of the art of nanocrystals-Special features, production, nanotoxicology aspects and intracellular delivery","volume":"78","author":"Gohla","year":"2011","journal-title":"Eur. 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