Predicting the Risk of Crystallization for Suspensions of Amorphous Spray Dried Dispersions from Structural, Thermal and Hydrophilicity Properties

Abstract

Suspensions of spray dried amorphous dispersions are a valuable tool for enhancing the exposure of poorly soluble compounds in preclinical animal models. However, limitations in drug supply and time/cost of manufacture in the drug discovery space make it desirable to predict the likelihood of obtaining a physically stable (free from detectable crystallization) suspension prior to synthetic scale-up and processing of a candidate compound. Background information on this topic is covered in Chapter 1. For 33.3% drug load solid dispersions in Hydroxypropylmethyl cellulose acetate succinate (HPMCAS) suspended in 0.5% Methocel + 0.25% sodium lauryl sulfate (SLS) + 5 mM HCl, a platform formulation frequently used in discovery, a 2-tiered model can be used to correctly predict the stability of 22 of 24 model compounds. First, the model considers the humidity adjusted glass transition temperature of the solid dispersion (Tg,dispersion,100% RH). For compounds where Tg,dispersion,100% RH is >30 °C, the dispersion is typically free from crystallization within 3 hours of preparation, which is attributed to a decrease in molecular mobility. 3 hours was selected as the timeframe between suspension preparation and dosing for the purpose of the present research. For compounds where Tg,dispersion,100% RH is 30 °C, the dispersion is typically free from crystallization within 3 hours of preparation, which is attributed to a decrease in molecular mobility. 3 hours was selected as the timeframe between suspension preparation and dosing for the purpose of the present research. For compounds where Tg,dispersion,100% RH is 1000 to be predicted stable) can be used to successfully predict a 3 hour shelf-life.