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Effect of Compression on Non-isothermal Crystallization Behaviour of Amorphous Indomethacin

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ABSTRACT

Purpose

To evaluate the effect of tablet compression on the physical stability of amorphous indomethacin.

Methods

The amorphous indomethacin generated by melt cooling, rapid (5°C/min) or slow (0.2°C/min) cooling, was evaluated by PXRD, mDSC and FTIR analysis. Non-isothermal crystallisation behaviour was assessed using mDSC and any structural changes with compression were monitored by FTIR. Amorphous indomethacin was compressed in a DSC pan using a custom made die cavity-punch setup and further analysed in the primary container to minimize stress due to sample transfer and preparation.

Results

Compression of amorphous indomethacin induced and increased the extent of crystallisation upon heating. DSC results revealed that amorphous indomethacin generated by rapid cooling is more prone to compression induced crystallisation than the slowly cooled one. Onset temperature for crystallisation (T c ) of uncompressed slowly and rapidly cooled samples are 121.4 and 124°C and after compression T c decreased to ca 109 and ca 113°C, respectively. Compression of non-aged samples led to higher extent of crystallisation predominantly into γ-form. Aging followed by compression led to crystallisation of mainly the α-form.

Conclusions

Compression affects the physical stability of amorphous indomethacin. Structural changes originated from tablet compression should be duly investigated for the stable amorphous formulation development.

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Abbreviations

DT:

dwell time

FTIR (ATR):

Fourier transform infrared spectroscopy (Attenuated total reflectance)

m:

minute

mDSC:

modulated differential scanning calorimetry

PMMA:

poly(methyl methacrylate)

PXRD:

powder x-ray diffraction

T c :

onset temperature for crystallisation

T g :

glass transition temperature

TSDC:

thermally stimulated depolarization current spectroscopy

ΔC p :

heat capacity change

ΔH c :

heat of crystallization

ΔH f (α) :

melting enthalpy of α-form

ΔH f (γ) :

melting enthalpy of γ-form

ΔH rec :

enthalpy recovery

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ACKNOWLEDGMENTS AND DISCLOSURES

ZA is grateful for the financial support of IRO, KU Leuven. AP also acknowledges D.B.O.F., KU Leuven, for providing a PhD grant. Department of Metallurgy and Materials Engineering (MTM), KU Leuven is also greatly acknowledged for providing facility for the ATR-FTIR.

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Authors and Affiliations

  1. Laboratory for Pharmacotechnology and Biopharmacy, KU Leuven, Herestraat 49, bus 921, 3000, Leuven, Belgium

    Zelalem Ayenew, Amrit Paudel, Patrick Rombaut & Guy Van den Mooter

Authors
  1. Zelalem Ayenew
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  2. Amrit Paudel
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  3. Patrick Rombaut
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  4. Guy Van den Mooter
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Correspondence to Guy Van den Mooter.

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Ayenew, Z., Paudel, A., Rombaut, P. et al. Effect of Compression on Non-isothermal Crystallization Behaviour of Amorphous Indomethacin. Pharm Res 29, 2489–2498 (2012). https://doi.org/10.1007/s11095-012-0778-5

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  • DOI: https://doi.org/10.1007/s11095-012-0778-5

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