Indomethacin (IND) is one of the supporting drug candidates for colonic targeting but it belongs to BCS class II category presenting a challenge in optimal targeting at the colonic site. To overcome this challenge, we sought to prepare a pH-dependent soluble ternary solid dispersion (SD) of IND of improved solubility and dissolution rate at the colon without the need for a coating. The current study focuses on the preparation of binary SDs of API (IND) with shellac (SSB 55) and Eudragit FS 100 (EFS) and ternary mixtures of IND, SSB 55 together with a new grade of HPMC (A15). Respective SDs were prepared via HME to achieve gastric protection and improved dissolution performance including maintenance of supersaturation. The SDs were characterized and tested for in-vitro dissolution performance using a pH shift dissolution method from 1.1, 5.5, 6.8, and 7.4. A ternary extrudate of IND, SSB 55, and A15 showed improved protection below pH 5.5 with a complete release of 99.5% at pH 7.4 compared to IND neat and binary extrudates from IND-A15, IND-SSB 55, and IND-EFS. It was attributed to an increased level of intermolecular interaction confirmed by ATR-IR and was studied for stability. It was found that in a ternary mixture containing IND, A15 and SSB 55 an increased hydrogen bonding interaction is present, which resulted in improved dissolution performance compared to binary mixtures. Therefore, ternary SDs proved to be a promising concept for future development of colon targeting of poorly soluble drugs.