Solid-State NMR Investigation of Drug-Excipient Interactions and Phase Behavior in Indomethacin-Eudragit E Amorphous Solid Dispersions
To investigate the nature of drug-excipient interactions between indomethacin (IMC) and methacrylate copolymer Eudragit® E (EE)
in the amorphous state, and evaluate the effects on formulation and stability of these amorphous systems.
Amorphous solid dispersions containing IMC and EE were spray dried with drug loadings from 20% to 90%. PXRD was used to confirm the amorphous nature of the dispersions, and DSC was used to
measure glass transition temperatures (Tg). 13C and 15N solid-state NMR was utilized to investigate changes in local structure and
protonation state, while 1H T1 and T1ρ relaxation measurements
were used to probe miscibility and phase behavior of the dispersions.
Tg values for IMC-EE solid dispersions showed significant positive
deviations from predicted values in the drug loading range of 40–90%, indicating a relatively strong drug-excipient interaction. 15N solid-state NMR exhibited a change in protonation state of the EE basic amine,
with two distinct populations for the EE amine at −360.7 ppm (unprotonated) and −344.4 ppm (protonated). Additionally, 1H relaxation measurements showed phase separation at high drug load, indicating an
amorphous ionic complex and free IMC-rich phase. PXRD data showed all ASDs up to 90% drug load remained physically stable after 2 years.
15N solid-state NMR experiments show a change in protonation state of
EE, indicating that an ionic complex indeed forms between IMC and EE in amorphous solid dispersions. Phase behavior was determined to exhibit nanoscale phase separation at high drug load
between the amorphous ionic complex and excess free IMC.