A Simple Non-Linear Kinetic Model to Evaluate Stability of a Pressure Sensitive Drug.

Candesartan cilexetil is challenging to formulate due to pressure induced chemical degradation. We report a statistical model based on stability data set of a marketed tablet formulation. Impurity increase over time was fitted to a reparametrized second-order kinetic model. Both kinetic model parameters have mechanistic interpretation: parameter a relates to the overall extent of pressure induced instability (the ceiling impurity level) and parameter b relates to the initial rate of degradation (how fast the ceiling is reached). A hierarchical model was then used to quantify sensitivity to tableting pressure and humidity-corrected Arrhenius equation quantified sensitivity to temperature and moisture. An overall model, based on four predictors and five estimated parameters allowed fitting of the entire stability dataset (694 stability data points) with good accuracy. Learnings allowed development of a stable formulation (soft tableting, increasing tablet size/shape and reducing moisture) and resulted in a confident stress stability test to evaluate any future product changes in a timely manner.