Reversible and pH-dependent weak drug-excipient binding does not affect oral bioavailability of high dose drugs

Objectives Drug-excipient binding can affect in-vitro drug release. Literature suggests that drug-excipient ionic binding interaction that is not disrupted by physiological salt concentration in the dissolution medium can impact a drug's oral bioavailability. We investigated whether nondisruption of interaction by physiological salt concentration was an adequate predictor of its biorelevance using the binding of a model amine high dose drug brivanib alaninate (BA) to croscarmellose sodium (CCS) as an example. Methods BA was formulated into an immediate release tablet using CCS as disintegrant by awet granulation process. In-vitro drug release was carried out as a function of pH and buffer concentration of the medium. BA-CCS binding was studied in buffer solution and data fitted to a Langmuir isotherm. A simulation model and an isothermal titration calorimetrymethod were developed to assess the bioavailability risk and strength of drug-excipient binding interaction, independent of physiological salt concentration consideration. Key findings BA-CCS binding was pH-dependent, reversible, ionic, and not disrupted by increasing the buffer concentration in the dissolution medium. Absorption simulation predictions of no effect of CCS binding on BA's bioavailability were confirmed by amonkey pharmacokinetic study. Conclusions A pH-dependent and reversible weak drug-excipient binding interaction is unlikely to affect the oral bioavailability of high dose drugs.