Structure-Function Relationships in Polysaccharide-Iron Complexes: Molecular Characterization, Acid-Stress Release...

Background: Polysaccharide-iron 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-function 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.