Dehydration and Stabilization of a Reactive Tertiary Hydroxyl Group in Solid Oral Dosage Forms of BMS 779788.
BMS 779788 contains a reactive tertiary hydroxyl attached to a weakly basic imidazole ring. Propensity of the carbinol toward dehydration to yield the corresponding alkene, BMS 779788 ALK, was evaluated. Elevated levels of BMS 779788 ALK were observed in excipient compatibility samples. Stability studies revealed that BMS 779788 degrades to BMS 779788 ALK in capsules and tablets prepared by both dry and wet granulation processes. An acid catalyzed dehydration mechanism, in which the heterocyclic core contributes resonance stability to the cationic intermediate via charge transfer to the imidazole ring, was proposed. Therefore, neutralization via a buffered (pH 7.0) granulating solution was used to mitigate dehydration. Solution studies revealed degradation of BMS 779788 to BMS 779788 ALK over the pH range of 1 7.5. Reversibility was confirmed by initiating reactions with BMS 779788 ALK over the same pH range. Accordingly, a simple reversible scheme can be used to describe reactions initiated with either BMS 779788 or BMS 779788 ALK. To eliminate potential for charge delocalization across the heterocycle and probe the degradation mechanism, the imidazole ring of BMS 779788 was methylated (BMS 779788 Me) The propensity for acid catalyzed dehydration was then evaluated. The acid stability of BMS 779788 Me confirmed that the heterocyclic core contributes to reactivity liability of the tertiary hydroxyl.
Journal of pharmaceutical sciences