Physical stability of amorphous solid dispersions : historical examples and shelf-life extrapolation

Amorphous solid dispersions (ASDs) of a poorly water-soluble active pharmaceutical ingredient (API) in a polymer matrix can enhance the water solubility and improve the bioavailability of the API. Many ASD products are kinetically stabilized, and the inhibition of crystallization of an API within and beyond shelf life is still a matter of debate, since the formation of crystals may impact bioavailability. We present the first literature examples of ASD long-term stability studies over up to 25 years under ambient storage conditions where no API crystallization was observed. Additionally, a risk assessment and mitigation strategy of API crystallization in packaged ASD drug products (DP) is outlined. The risk of shelf-life crystallization and the respective mitigation steps are assigned for different DP development scenarios. Ultimately, the physical stability of ASD DPs during shelf-life storage is modeled by quantifying crystal growth kinetics by transmission Raman spectroscopy (TRS), modeling the impact of water sorption on the glass-transition temperature of the ASD, and predicting the moisture uptake by the packaged ASD DP during storage. This approach is applied to an ASD of an AbbVie-internal compound showing stability beyond the anticipated shelf-life.