Drug-plasticizer interactions causing solid state transitions of rifaximin

Solid phase interactions are often the reason for incompatibilities in solid dosage forms. A special situation occurs, if the incompatible compounds are able to migrate within the solid matrix. This study describes for the first time the migration of a plasticizer from the coating into the core and its interaction with the active ingredient located there. This behavior was observed in rifaximin gastro-resistant granules and resulted in the formation of solvates with altered dissolution behavior. For a detailed study, rifaximin was incubated with five plasticizers of different solubility and miscibility as well as different molecular geometry (linear vs branched), (dibutyl sebacate, tributyl citrate, triacetin, polyethylene glycol 400, and propylene glycol). The resulting solid states were analyzed by means of PXRD, supported by thermogravimetric analysis, infrared spectroscopy, and quantitative H NMR. No direct correlation could be demonstrated between the resulting type of solvate/hydrate and the affinity of rifaximin with the respective plasticizers. Interestingly all plasticizers that are able to form type I solvates/hydrates have linear structures. This common feature, which distinguishes them from the more bulky TAC and TBC, seems to be a key characteristic. Rifaximin-PG-solvate formation was not only detected after direct incubation trials, but also observed in enteric coated granules.