Interaction of Bay t 3839 coprecipitates with insoluble excipients

Bay t 3839 is an extremely sparingly soluble drug and results in severe problems with regard to oral bioavailability. In order to improve the dissolution performance a coprecipitate formulation approach was investigated and the necessary ratio polyvinylpyrrolidone (pvp) to drug substance was found to be approximately 15 in order to achieve a sufficient supersaturation in 900 ml 0.1 N HCl, which is considered to be an appropriate as well as challenging in vitro test method. Surprisingly substantial differences in the dissolution characteristics of coprecipitate granulates were revealed when the coprecipitate was formed on excipients which was not the case when pure pvp/drug coprecipitates were submitted to dissolution testing. As substantial deterioration of the supersaturation capability was detected only in the case of insoluble excipients it is concluded that solid/liquid interfaces during the dissolution step act as recrystallization inducers. In case of soluble fillers/adsorbents, like mannitol, the supersaturation capability could be maintained also after the granulation step. Therefore, it is likely that in the case of extremely challenging drug candidates like, e.g. Bay t 3839, the supersaturated solution is less stable than in the case of more soluble compounds. These more susceptible coprecipitates can be stabilized by proper selection of the granulation excipients. Additionally the admixture of crystallization inhibiting agents like sodium dodecyl sulfate (SDS) offers the opportunity to decrease the necessary ratio pvp/Bay t 3839 considerably (to a ratio of approximately 7).