Pharmaceutical multi-component solid forms, including salts, co-crystals and co-amorphous systems (COAMs), are used to modify the physicochemical and pharmaco-kinetic properties of these drugs. Gefitinib and two co-formers, bumetanide and furosemide, form salt hydrates in the presence of water and COAMs in the absence of water using solvent evaporation method. Molecular dynamic simulation and isolated water analysis reveal that water molecules play a multi-faceted role in stabilizing the crystalline salt hydrate systems by reducing the total energy of the system, establishing hydrogen bonds, and maintaining the crystalline 3D structures. Salt hydrates are also formed in the presence of water using liquid-assisted grinding. In the absence of water, intermolecular interactions between Gefitinib and co-formers facilitate the formation of COAMs during ball milling and quench cooling, i.e., in the absence of water. These findings provide valuable insights to the formation of salt hydrates and COAMs by controlling the presence of water.