{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T22:34:32Z","timestamp":1791758072320,"version":"4.3.4"},"reference-count":65,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Generalitat of Catalonia, Industrial Doctorate Program","award":["2022 DI 015"],"award-info":[{"award-number":["2022 DI 015"]}]},{"name":"Generalitat of Catalonia, Industrial Doctorate Program","award":["2023 DI 050"],"award-info":[{"award-number":["2023 DI 050"]}]},{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"crossref","award":["101057668"],"award-info":[{"award-number":["101057668"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Liposomes are attractive topical carriers, yet translating laboratory fabrication to scalable, well-controlled processes remains challenging. Objectives: We compared three manufacturing methods for diclofenac-loaded liposomes: probe sonication, microfluidic mixing, and a high-turbulence microreactor, under a Quality-by-Design framework. Methods: Differential scanning calorimetry (DSC) was used to define a processing-relevant liquid-crystalline temperature window for the lipid excipients. For sonication scale-up, a Plackett-Burman screening design identified key process factors and supported an energy-density (W\u00b7s\u00b7L\u22121) control approach. For microfluidics, the effects of flow-rate ratio (FRR) and total flow rate (TFR) were mapped and optimized using a desirability function. Microreactor trials were performed at elevated throughput. Residual ethanol during post-processing was monitored at-line by Raman spectroscopy calibrated against gas chromatography (GC). Particle size and dispersity were measured by DLS and morphology assessed by cryo-TEM. Results: DSC supported a 70\u201385 \u00b0C processing window. Sonication scale-up using an energy-density target (~11,000 W\u00b7s\u00b7L\u22121) reproduced lab-scale quality at 8 L (Z-average ~87\u201392 nm; PDI 0.16\u20130.23; %EE 86\u201394%). Microfluidics optimization selected FRR 3:1\/TFR 4 mL\u00b7min\u22121, yielding ~64 nm liposomes with PDI ~0.13 and %EE ~93%. The microreactor achieved ~50 nm liposomes with %EE ~95% at 50 mL\u00b7min\u22121. Cryo-TEM corroborated size trends and showed no evident aggregates. Conclusions: All three routes met topical CQAs (~50\u2013100 nm; PDI \u2264 0.30; high %EE). Method selection should be guided by target size\/dispersity and operational constraints: sonication enables energy-based scale-up, microfluidics offers precise size control, and microreactors provide higher throughput.<\/jats:p>","DOI":"10.3390\/pharmaceutics18010105","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T15:52:57Z","timestamp":1768319577000},"page":"105","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Comparative Analysis of Sonication, Microfluidics, and High-Turbulence Microreactors for the Fabrication and Scaling-Up of Diclofenac-Loaded Liposomes"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5026-1311","authenticated-orcid":false,"given":"Iria","family":"Naveira-Souto","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Pharmaceutical Innovation, Reig Jofre Laboratories, 08970 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0023-8709","authenticated-orcid":false,"given":"Roger","family":"Fabrega Alsina","sequence":"additional","affiliation":[{"name":"Pharmaceutical Development, Reig Jofre Laboratories, 08970 Barcelona, Spain"},{"name":"Nanobioengineering, Institute for Bioengineering of Catalonia (IBEC), 08028 Barcelona, Spain"},{"name":"Doctorate Program in Biomedicine, University of Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8230-0474","authenticated-orcid":false,"given":"Elisabet","family":"Rosell-Vives","sequence":"additional","affiliation":[{"name":"Pharmaceutical Innovation, Reig Jofre Laboratories, 08970 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8743-7229","authenticated-orcid":false,"given":"Eloy","family":"Pena-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Pharmaceutical Innovation, Reig Jofre Laboratories, 08970 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8224-2932","authenticated-orcid":false,"given":"Francisco","family":"Fernandez-Campos","sequence":"additional","affiliation":[{"name":"Pharmaceutical Innovation, Reig Jofre Laboratories, 08970 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Malavia","sequence":"additional","affiliation":[{"name":"Pharmaceutical Development, Reig Jofre Laboratories, 08970 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xavier","family":"Julia Camprodon","sequence":"additional","affiliation":[{"name":"Pharmaceutical Innovation, Reig Jofre Laboratories, 08970 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Schelden","sequence":"additional","affiliation":[{"name":"MyBiotech GmbH, Industriestr. 1b, 66802 \u00dcberherrn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6310-4785","authenticated-orcid":false,"given":"Nazende","family":"G\u00fcnday-T\u00fcreli","sequence":"additional","affiliation":[{"name":"MyBiotech GmbH, Industriestr. 1b, 66802 \u00dcberherrn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1565-0992","authenticated-orcid":false,"given":"Andr\u00e9s","family":"Cruz-Conesa","sequence":"additional","affiliation":[{"name":"IRIS Technology Solutions, 08940 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4080-3516","authenticated-orcid":false,"given":"Maria","family":"Lajarin-Reinares","sequence":"additional","affiliation":[{"name":"Pharmaceutical Innovation, Reig Jofre Laboratories, 08970 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.ijpharm.2012.12.041","article-title":"Inhibition of Skin Inflammation in Mice by Diclofenac in Vesicular Carriers: Liposomes, Ethosomes and PEVs","volume":"443","author":"Caddeo","year":"2013","journal-title":"Int. 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