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Solid-State NMR Investigation of Drug-Excipient Interactions and Phase Behavior in Indomethacin-Eudragit E Amorphous Solid Dispersions

  • Research Paper
  • Theme: Formulation and Manufacturing of Solid Dosage Forms
  • Published:
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Abstract

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 (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.

Results

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.

Conclusions

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.

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Abbreviations

ASD:

Amorphous solid dispersion

CP:

Cross polarization

DSC:

Differential scanning calorimetry

EE:

Eudragit® E

FTIR:

Fourier transform infrared spectroscopy

HPMCAS:

Hydroxypropyl methylcellulose acetate succinate

HPMCP:

Hydroxypropyl methylcellulose phthalate

IMC:

Indomethacin

MAS:

Magic-angle spinning

NMR:

Nuclear magnetic resonance spectroscopy

PSSA:

Polystyrene sulfonic acid

PVP:

Poly(vinylpyrrolidone)

PVPVA:

Poly(vinylpyrrolidone-co-vinyl acetate)

PXRD:

Powder X-ray diffraction

RF:

Radiofrequency

TOSS:

Total sideband suppression

UV:

Ultraviolet spectroscopy

XPS:

X-ray photoelectron spectroscopy

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Authors and Affiliations

  1. Small Molecule Pharmaceutical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080, USA

    Joseph W. Lubach & Jonathan Hau

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  1. Joseph W. Lubach
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Correspondence to Joseph W. Lubach.

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Guest Editors: Tony Zhou and Tonglei Li

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Lubach, J.W., Hau, J. Solid-State NMR Investigation of Drug-Excipient Interactions and Phase Behavior in Indomethacin-Eudragit E Amorphous Solid Dispersions. Pharm Res 35, 65 (2018). https://doi.org/10.1007/s11095-018-2364-y

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  • DOI: https://doi.org/10.1007/s11095-018-2364-y

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