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To overcome these challenges, two novel formulations\u2014liposomal doxorubicin (Dox-Lip) and proliposomal doxorubicin (Dox-P-Lip) \u2014were developed and systematically compared with the reference listed drug (RLD), focusing on physicochemical comparability and\n                    <jats:italic>in vitro<\/jats:italic>\n                    bioequivalence in accordance with FDA guidance. Dox-Lip was prepared using alternative lipid compositions and a modified pH gradient\u2013based active loading method, while Dox-P-Lip was obtained by lyophilization of the liposomal formulation. Characterization studies included encapsulation efficiency (EE%), lipid content, drug-to-lipid ratio, internal pH, morphology, bilayer phase behavior, PEG surface density, particle size, zeta potential, and PEG layer thickness determined using the Fixed Aqueous Layer Thickness (FALT) model.\n                    <jats:italic>In vitro<\/jats:italic>\n                    drug release was evaluated under simulated plasma, variable pH and temperature, and ultrasound exposure. Both formulations exhibited high encapsulation efficiencies (EE%) exceeding 90%, comparable to those of the RLD. Moreover, these formulations demonstrated approximately 2.1-fold thicker PEG layers, indicating improved steric stabilization. Although these formulations exhibited slightly higher leakage under stress conditions, the encapsulation efficiency (EE%) consistently remained above 90%, confirming their structural integrity. Overall, the novel formulations demonstrated physicochemical similarity and stability relative to the RLD, supporting their potential as bioequivalent and clinically viable liposomal Dox alternatives.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1208\/s12249-026-03357-y","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T21:09:54Z","timestamp":1770844194000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Physicochemical Characterization and In Vitro Evaluation of Novel Liposomal and Proliposomal Doxorubicin Formulations in Accordance with FDA Guidance"],"prefix":"10.1208","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8601-0263","authenticated-orcid":false,"given":"G\u00fclbeyaz","family":"Y\u0131ld\u0131z T\u00fcrky\u0131lmaz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7154-8511","authenticated-orcid":false,"given":"Mine","family":"Diril","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1860-8255","authenticated-orcid":false,"given":"H. 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