K+-directed co-assembly of alginate and gellan gum enables coating-free enteric HPMC hard capsules with programmed drug releases

Enteric hard capsules are conventionally manufactured by applying coatings to pre-formed shells, a process requiring stringent control. Here, we report a strategy to directly integrate enteric functionality into hydroxypropyl methylcellulose (HPMC)-based hard capsules using an ion-regulated supramolecular gel composed of sodium alginate (SA) and gellan gum (GG). Potassium ions (K + ) direct the co-assembly of SA and GG by screening charges, coordinating with carboxylate groups, and reorganizing the hydrogen-bonding network. A multiscale approach, combining microscopy, spectroscopy, and simulations, reveals that SA and GG chains co-assemble primarily through hydrogen bonding into aligned aggregates. K + consolidates the network, reducing intermolecular distances and promoting fibrillar coarsening with fiber alignment. This yields a compact structure with enhanced mechanical strength and pH responsiveness. An optimized formulation (SA:GG = 0.7:0.4 wt% with 0.35 wt% K + ) exhibits stable viscoelasticity and suitable gelation kinetics, enabling reproducible capsule fabrication. Dissolution tests confirm gastric resistance at pH 1.2 for 2 h and rapid disintegration at intestinal pH 6.8, with >80% drug release within 45 min. Moisture-sorption modeling demonstrates that gastric resistance is retained after storage, with early-stage absorption being diffusion-dominated (apparent diffusion coefficient ca. 10 −5  mm 2 ·h −1 ). By linking ion-regulated molecular assembly to targeted enteric performance, this polysaccharide-based strategy offers a scalable, green platform for next-generation hard capsules, eliminating solvent-intensive coating and advancing sustainable manufacturing. Download: Download high-res image (261KB) Download: Download full-size image