Due to the existence of stoppers on the ends of the rotaxanes units, polyrotaxanes are more thermodynamically stable than polypseudorotaxanes (similar structure to polyrotaxane but without stoppers at two ends). Also, if the interactions between guest and host molecules are attractive, such as hydrogen bonding or charge transfer, they have better stabilities than those without attractive interactions. However, specific salts, changes of pH condition or temperature that can disturb or interrupt the interactions between ring-ring, ring-backbone, or backbone-backbone will destroy the structural integrity of polyrotaxanes. For example, dimethylformamide or dimethyl sulfoxide is able to interrupt the hydrogen bonding between cyclodextrins in the cyclodextrin-based polyrotaxanes. Also, change of pH or high temperature can also destroy the crystalline domains. Some chemical bonds between stoppers and chains are not stable in acidic or basic solution. As the stoppers cut from the chain, the rings will dethread from the axles, which leads to the dissociation of the polyrotaxanes.
For example, a "molecular necklace" assembled by α-cyclodextrins and polyethylene glycol is insoluble in water and dimethylfomamide, although their parents' components α-cyclodextrin and polyethylene glycol can be dissolved and this synthesis can happen in water. The product is soluble in dimethyl sulfoxide or 0.1 M sodium hydroxide solution. This is because the hydrogen bonding between the cyclodextrins. As the hydrogen bonding is destroyed by dimethyl sulfoxide or base solution, it can be dissolved, but the water does not deform the hydrogen interaction between cyclodextrins. In addition, the complexation process is exothermic in thermodynamic tests, which is also corresponding with the existence of hydrogen bonding.