orabase and brivanib

Real-time monitoring and control of high shear wet granulation (HSWG) using process analytical technologies is crucial to process design, scale-up, and reproducible manufacture. Although significant progress has been made in real-time measurement of granule size distribution using focused beam reflectance measurement (FBRM), real-time in-line assessment of granule densification remains challenging. In this study, a drag force flow (DFF) sensor was developed and used to probe wet mass consistency in real-time. In addition, responses from FBRM and DFF sensors were compared to assess complementarity of information on granulation progress from the two probes. A placebo and a brivanib alaninate formulation were granulated with different concentrations of binder or water, respectively, while measuring granule size growth, densification, and DFF sensor response. The DFF sensor was able to quantitatively characterize with high resolution a response of wet mass consistency distinct from granule size distribution. The wet mass consistency parameter correlated well with granule densification, which was shown as a critical material attribute that correlated with tablet dissolution. In addition, application of DFF sensor to scale-up of granulation was demonstrated. These results showed the value of wet mass consistency measurement using DFF for WG monitoring and control.

Topics: Administration, Oral; Alanine; Carboxymethylcellulose Sodium; Cellulose; Chemistry, Pharmaceutical; Equipment Design; Excipients; Kinetics; Lactose; Models, Chemical; Models, Statistical; Particle Size; Placebos; Porosity; Powders; Quality Control; Solubility; Tablets; Technology, Pharmaceutical; Triazines; Water

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.. BA was formulated into an immediate release tablet using CCS as disintegrant by a wet 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 calorimetry method were developed to assess the bioavailability risk and strength of drug-excipient binding interaction, independent of physiological salt concentration consideration.. 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 a monkey pharmacokinetic study.. A pH-dependent and reversible weak drug-excipient binding interaction is unlikely to affect the oral bioavailability of high dose drugs.

Topics: Administration, Oral; Alanine; Animals; Biological Availability; Buffers; Calorimetry; Carboxymethylcellulose Sodium; Drug Interactions; Excipients; Hydrogen-Ion Concentration; Macaca fascicularis; Male; Models, Biological; Tablets; Triazines