{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T14:05:05Z","timestamp":1784729105725,"version":"3.55.0"},"reference-count":34,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Polysaccharide\u2013iron complexes (PICs) are widely used oral iron supplements, but their gastrointestinal tolerability varies and remains incompletely understood. As typical non-biological complex drugs (NBCDs), PICs exhibit structural heterogeneity, and their functional performance may be linked to higher-order structural attributes. Methods: In this study, two commercial PIC preparations (test samples A and B) were comparatively investigated to explore their structure\u2013function relationship using a multi-dimensional approach. Structural properties were characterized by gel permeation chromatography (GPC), mass spectrometry (MS), Fourier-transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR) spectroscopy, along with monosaccharide composition analysis. Functional behaviors and physiological relevance were further evaluated through in vitro acid-stress release studies and in vivo rat gastrointestinal tolerability assessments. Results: The results revealed that test sample A exhibited a glucose-only detectable monosaccharide profile but a higher and broader apparent molecular-weight distribution, indicating monosaccharide compositional uniformity together with macromolecular heterogeneity. In contrast, test sample B showed detectable glucose and mannose, a lower and narrower apparent molecular-weight distribution, higher measured free iron, and greater iron release under the tested acidic conditions. An exploratory 7-day rat gastrointestinal tolerability study (n = 4 per group) indicated that these distinct profiles may impact mucosal tolerability. Structurally stable test sample A allowed intestinal iron accumulation while maintaining mucosal integrity. Conversely, the rapid dissociation of test sample B induced observable mucosal injury, despite lower local iron retention. Conclusions: These findings suggest that the gastrointestinal tolerability of PICs may be associated with their structural attributes and release behavior, rather than total iron content alone. Overall, this exploratory study highlights a potential relationship between multi-dimensional PIC structure and functional performance, emphasizing the need for broader, structure-informed frameworks in the quality evaluation of complex iron therapies.<\/jats:p>","DOI":"10.3390\/pharmaceutics18070896","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T16:16:39Z","timestamp":1784650599000},"page":"896","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structure\u2013Function Relationships in Polysaccharide\u2013Iron Complexes: Molecular Characterization, Acid-Stress Release Stability, and Gastrointestinal Tolerability"],"prefix":"10.3390","volume":"18","author":[{"given":"Xiangqiu","family":"Qi","sequence":"first","affiliation":[{"name":"Quzhou Fudan Institute, Quzhou 324002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwei","family":"Zhu","sequence":"additional","affiliation":[{"name":"Quzhou Fudan Institute, Quzhou 324002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Yan","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Fudan University, Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Kang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Fudan University, Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Xiao","sequence":"additional","affiliation":[{"name":"The Second People\u2019s Hospital of Quzhou, Quzhou 324000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianyi","family":"Sha","sequence":"additional","affiliation":[{"name":"Quzhou Fudan Institute, Quzhou 324002, China"},{"name":"School of Pharmacy, Fudan University, Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kolar\u0161, B., Mijatovi\u0107 Jovin, V., \u017divanovi\u0107, N., Minakovi\u0107, I., Gvozdenovi\u0107, N., Dickov Kokeza, I., and Lesjak, M. 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