(402b) Mathematical Models for the Stability of Atropisomer-Forming Drug Substance in a Spray-Dried Dispersion Formulation

Spray dried dispersions are commonly implemented to enhanced the delivery properties of many oral dosage drug products. Despite their favorable absorption profiles, adoption of this formulation may result in a drug product of decreased physical or chemical stability compared to formulations incorporating a crystalline form of the API. Predicting the long term stability of SDD’s under ICH recommended storage conditions is generally required in order to establish appropriate control strategies, determine target specification, and toxicological qualification limits to enable a viable commercial formulation. We describe the development of a mathematical model to quantify the rate of atropisomer interconversion in the SDD drug product of a chiral compound with four potential atropisomers. The interconversion kinetics in the liquid state were adequately described by the Wei-Pratter formalism, however in the amorphous dispersion the kinetics followed a Kohlrausch-William-Watts stretched exponent function. The KWW model was used to establish expectations on the observable levels following prolonged storage. Bayesian analysis was incorporated to quantify the risk of Out of Specification instances following commercialization of the product. Stretched exponent functions are recurrent in the kinetic phenomena in the amorphous state therefore this formalism can be extended to address the risk of SDD formulations from early accelerated stability data.