Solid-State NMR Investigation of Drug-Excipient Interactions and Phase Behavior in Indomethacin-Eudragit E Amorphous Solid Dispersions
Purpose 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. Methods Amorphous solid dispersions containing IMC and EE...
Saved in:
Published in | Pharmaceutical research Vol. 35; no. 3; pp. 65 - 11 |
---|---|
Main Authors | , |
Format | Journal Article |
Language | English |
Published |
New York
Springer US
01.03.2018
Springer Springer Nature B.V |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | Purpose
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.
Methods
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 (
T
g
).
13
C and
15
N solid-state NMR was utilized to investigate changes in local structure and protonation state, while
1
H
T
1
and
T
1ρ
relaxation measurements were used to probe miscibility and phase behavior of the dispersions.
Results
T
g
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.
15
N 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,
1
H 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.
Conclusions
15
N 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. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0724-8741 1573-904X |
DOI: | 10.1007/s11095-018-2364-y |