Understanding the Influence of API Conformations on Amorphous Dispersion Formation Potential Predictions using the R 3 m Molecular Descriptor.

The R 3 m molecular descriptor (R-GETAWAY third-order autocorrelation index weighted by the atomic mass) has previously been shown to encode molecular attributes that appear to be physically and chemically relevant to grouping diverse active pharmaceutical ingredients (API) according to their potential to form persistent amorphous solid dispersions (ASDs) with polyvinylpyrrolidone-vinyl acetate copolymer (PVPVA). The initial R 3 m dispersibility model was built by using a single three-dimensional (3D) conformation for each drug molecule. Since molecules in the amorphous state will adopt a distribution of conformations, molecular dynamics simulations were performed to sample conformations that are probable in the amorphous form, which resulted in a distribution of R 3 m values for each API. Although different conformations displayed R 3 m values that differed by as much as 0.4, the median of each R 3 m distribution and the value predicted from the single 3D conformation were very similar for most structures studied. The variability in R 3 m resulting from the distribution of conformations was incorporated into a logistic regression model for the prediction of ASD formation in PVPVA, which resulted in a refinement of the classification boundary relative to the model that only incorporated a single conformation of each API.