Enhancement of dissolution performance of amorphous solid dispersions by plasticization

The nanodroplets produced during ASD release can dissolve rapidly due to their small size and amorphous nature. The rapid dissolution of the nanodroplets may lead to a reservoir effect, replenishing drug removed by absorption and maintaining the maximum achievable flux across a membrane; however, because they are hydrophobic and small, there is a high tendency for size enlargement in aqueous media to form larger particles. If the nanodroplets have poor size stability, they may lose their reservoir effect, and may have a greater tendency to crystallize. Additionally, complete drug release and nanodroplet formation have been mainly reported for drug loadings (DL) below a threshold named the limit of congruency (LoC), which for some drugs can be as low as 5% drug loading.2,3The low drug loading may lead to a tablet burden or require multiple dosage units or, if higher drug loadings are used, insufficient drug exposure.

The ability of different surfactant to stabilize drug-rich nanodroplets against size enlargement was assessed herein. Additionally, the potential of surfactants and plasticizers to increase ASD drug loading without compromising release was evaluated for a low glass transition temperature (T_g) and a high T_g compound. Surface normalized dissolution of ternary ASDs with 5% w/w surfactant or plasticizer was evaluated. The addition of surfactant had little impact at increasing the DL of the low T_g compound but the nanodroplets formed were smaller. On the other hand, the LoC of the high T_g compound was increased up to 3 times and the total drug release was improved by as much as a factor of 30 compared to the binary ASD for the same DL. The results suggest that the low mobility of high T_g compounds is an important property limiting the drug release. Thus, surfactants have a plasticizing effect that increases the mobility and promotes drug release from ASDs.

To further test the impact of plasticizers, citric acid and glycerol derivatives which are well known plasticizers were added to ASDs formulated with high T_g compounds, with the goal of increasing the LoC. The use of 5 or 10% w/w of a plasticizer increased the LoC up to 5 times. Additionally, the release rate was up to twice as fast as that observed for the binary ASD. The dissolution rate was also increased for the neat polymer in the presence of the plasticizers while the water sorption kinetics were reduced. This suggests that polymer disentanglement rate was increased by the presence of the plasticizer.

These studies have significance for ASD formulations, especially in the systematic selection of additional excipients such as surfactants and plasticizers where the release performance can be significantly improved.