In Situ Salt Formation in a Solid SNEDDS: A Triple Solubilizing, Stabilizing, and Dose-Reducing Strategy Enabling Single-Capsule Glibenclamide Administration

Background/Objectives: Liquid self-nanoemulsifying drug delivery systems (L-SNEDDSs) efficiently improve oral bioavailability of poorly water-soluble drugs. However, adsorption onto mesoporous carriers often doubles the formulation mass and locks patients into multi-capsule regimens. This study aimed to develop a solid SNEDDS for glibenclamide (GLB), a weakly acidic, acid-labile, poorly soluble antidiabetic drug, using sodium carbonate as a multifunctional alkalizing excipient to enhance drug loading, improve chemical stability, and enable single-capsule administration. Methods: L-SNEDDSs were prepared using Tween 80, PEG 400, and Imwitor 308 (4:3:3, w/w). Sodium carbonate (Na2CO3) was benchmarked against triethanolamine as an alkalizing agent intended to promote in situ ionization (salt formation) of GLB. The optimized liquid was adsorbed onto Syloid (mesoporous silica) at a 1:1 (w/w) ratio to produce a free-flowing solid SNEDDS. Drug loading, dissolution, degradation kinetics at 40 °C and chemical stability at room temperature were evaluated. Results: Sodium carbonate incorporation significantly increased GLB solubility from 5.97 to 17.42 mg/g (2.9-fold increase, p < 0.01), outperforming triethanolamine (1.1-fold). The alkalized formulation extended the drug half-life at 40 °C from 12.4 to 30.1 days (2.4-fold, p < 0.01). Increasing drug loading in L-SNEDDSs from 5 to 15 mg/g maintained rapid in vitro dissolution, with >84% drug released within 10 min and similar dissolution efficiency (DE) across 5–15 mg/g despite tripling the drug content. The optimized solid (15 mg/g) achieved a 21.9-fold improvement in dissolution efficiency (p < 0.01) vs. raw drug. Moreover, it reduced total powder mass from 1000 to 333 mg and enabled single-capsule administration. Both liquid and solid alkalized SNEDDSs significantly enhanced GLB stability compared to the plain liquid SNEDDS. Conclusions: Overall, Na2CO3-enabled in situ ionization offers a practical, single-step approach to simultaneously mitigate poor solubility, acid-lability, and dose-volume limitations in solid SNEDDSs, providing a promising platform for improved oral delivery and potentially better patient adherence for weakly acidic, acid-labile drugs.