Purpose <p>We developed a modified-release fixed-dose combination (FDC) bilayer tablet that integrates an empagliflozin-L-proline (1:2) cocrystal into an immediate-release (IR) layer with a metformin hydrochloride sustained-release (SR) layer.</p> Methods <p>Cocrystals were prepared by solvent crystallization and characterized using powder X-ray diffraction, thermogravimetric analysis, and differential scanning calorimetry. The bilayer formulation was systematically optimized by formulation screening and in vitro dissolution evaluation. Dissolution similarity (f₂) was assessed against the reference products Jardiance 25&#xa0;mg and Glucophage XR 1000&#xa0;mg. The bioequivalence (BE) was evaluated in a randomized, two-period crossover study in healthy volunteers.</p> Results <p>Solid-state analyses confirmed the formation of a well-defined 1:2 cocrystal comprising one empagliflozin molecule and two L-proline molecules. The cocrystal exhibited complete dissolution across all evaluated pH conditions. Furthermore, it displayed solubility, chemical stability, and systemic exposure comparable with those of the empagliflozin-free base, suggesting that co-crystallization did not significantly alter the pharmacokinetic behavior. The optimized bilayer tablet demonstrated dissolution similarity (f₂ ≥ 50) to the reference products across all tested media. The clinical study demonstrated that the geometric mean ratios for AUC and C_max, with corresponding 90% confidence intervals, were within the accepted BE range of 80–125%.</p> Conclusion <p>The developed IR/SR bilayer FDC tablet displayed pharmaceutical robustness and clinical bioequivalence, demonstrating that cocrystals can be effectively integrated into complex modified release systems while maintaining bioequivalent in vivo performance. This study provides a translatable strategy for cocrystal-enabled FDC development and supports the application of solid-state engineering approaches for advanced oral drug delivery.</p>