Spatial confinement can lead to increased stability of amorphous indomethacin

Publication: Research - peer-reviewJournal article – Annual report year: 2012

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Spatial confinement can lead to increased stability of amorphous indomethacin. / Nielsen, Line Hagner; Keller, Stephan Sylvest; Gordon, Keith C.; Boisen, Anja; Rades, Thomas; Müllertz, Anette.

In: European Journal of Pharmaceutics and Biopharmaceutics, Vol. 81, No. 2, 2012, p. 418-425.

Publication: Research - peer-reviewJournal article – Annual report year: 2012

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Nielsen, Line Hagner; Keller, Stephan Sylvest; Gordon, Keith C.; Boisen, Anja; Rades, Thomas; Müllertz, Anette / Spatial confinement can lead to increased stability of amorphous indomethacin.

In: European Journal of Pharmaceutics and Biopharmaceutics, Vol. 81, No. 2, 2012, p. 418-425.

Publication: Research - peer-reviewJournal article – Annual report year: 2012

Bibtex

@article{28bc9c5601844a8eb47d2646a3ba9ab3,
title = "Spatial confinement can lead to increased stability of amorphous indomethacin",
keywords = "Indomethacin, Amorphous, Confinement, Physical stability, Raman microscopy",
publisher = "Elsevier BV",
author = "Nielsen, {Line Hagner} and Keller, {Stephan Sylvest} and Gordon, {Keith C.} and Anja Boisen and Thomas Rades and Anette Müllertz",
year = "2012",
doi = "10.1016/j.ejpb.2012.03.017",
volume = "81",
number = "2",
pages = "418--425",
journal = "European Journal of Pharmaceutics and Biopharmaceutics",
issn = "0939-6411",

}

RIS

TY - JOUR

T1 - Spatial confinement can lead to increased stability of amorphous indomethacin

A1 - Nielsen,Line Hagner

A1 - Keller,Stephan Sylvest

A1 - Gordon,Keith C.

A1 - Boisen,Anja

A1 - Rades,Thomas

A1 - Müllertz,Anette

AU - Nielsen,Line Hagner

AU - Keller,Stephan Sylvest

AU - Gordon,Keith C.

AU - Boisen,Anja

AU - Rades,Thomas

AU - Müllertz,Anette

PB - Elsevier BV

PY - 2012

Y1 - 2012

N2 - The aim of this study was to investigate whether the physical stability of amorphous indomethacin can be improved by separating the drug material into small units by the use of microcontainers. Crystallisation from the spatially confined amorphous indomethacin in the microcontainers was determined and compared with the crystallisation kinetics of amorphous bulk indomethacin.Amorphous indomethacin in both a bulk form and contained within microcontainers was prepared by melting of bulk or container-incorporated γ-indomethacin, respectively, followed by quench-cooling. Microcontainers of three different sizes (diameters of 73μm, 174μm and 223μm) were used for the confinement of amorphous indomethacin, in order to elucidate whether the size of the microcontainer had an influence on the stability of the amorphous form. Following preparation, all samples were stored at 30°C and 23% RH. A sample of 100 microcontainers of each size was selected and measured on a Raman microscope over a period of 30days to ascertain whether the indomethacin in each container was amorphous or crystalline. Over time, a crystallisation number was obtained for the amorphous indomethacin in the microcontainers. The crystallisation numbers from the microcontainers were compared with the crystallisation kinetics of the amorphous bulk indomethacin, as determined by FT-Raman spectroscopy.Comparison of the numeric crystallisation in the microcontainers with the crystallisation kinetics of the amorphous bulk indomethacin showed that spatial confinement of indomethacin led to a significantly lower extent of crystallisation of the amorphous form. In the 174μm microcontainers, 29.0±2.6% of the amorphous indomethacin crystallised to the stable γ-form over a period of 30days, whilst 38.3±1.5% of the amorphous indomethacin crystallised in the 223μm microcontainers. Both these values were significantly different from that observed in the amorphous bulk indomethacin, where 51.0% crystallised to the γ-form after 30days. Comparing the 174 and 223μm microcontainers also revealed a significantly greater stabilising effect of the 174μm microcontainers (p-value of 0.0061).Surprisingly, for microcontainers with an inner diameter of 73μm, no stability improvement was found when compared to amorphous bulk indomethacin. It was observed that the amorphous indomethacin within these containers converted to the α-form of indomethacin (a metastable polymorph) which was unexpected at the storage conditions at 30°C and 23% RH.

AB - The aim of this study was to investigate whether the physical stability of amorphous indomethacin can be improved by separating the drug material into small units by the use of microcontainers. Crystallisation from the spatially confined amorphous indomethacin in the microcontainers was determined and compared with the crystallisation kinetics of amorphous bulk indomethacin.Amorphous indomethacin in both a bulk form and contained within microcontainers was prepared by melting of bulk or container-incorporated γ-indomethacin, respectively, followed by quench-cooling. Microcontainers of three different sizes (diameters of 73μm, 174μm and 223μm) were used for the confinement of amorphous indomethacin, in order to elucidate whether the size of the microcontainer had an influence on the stability of the amorphous form. Following preparation, all samples were stored at 30°C and 23% RH. A sample of 100 microcontainers of each size was selected and measured on a Raman microscope over a period of 30days to ascertain whether the indomethacin in each container was amorphous or crystalline. Over time, a crystallisation number was obtained for the amorphous indomethacin in the microcontainers. The crystallisation numbers from the microcontainers were compared with the crystallisation kinetics of the amorphous bulk indomethacin, as determined by FT-Raman spectroscopy.Comparison of the numeric crystallisation in the microcontainers with the crystallisation kinetics of the amorphous bulk indomethacin showed that spatial confinement of indomethacin led to a significantly lower extent of crystallisation of the amorphous form. In the 174μm microcontainers, 29.0±2.6% of the amorphous indomethacin crystallised to the stable γ-form over a period of 30days, whilst 38.3±1.5% of the amorphous indomethacin crystallised in the 223μm microcontainers. Both these values were significantly different from that observed in the amorphous bulk indomethacin, where 51.0% crystallised to the γ-form after 30days. Comparing the 174 and 223μm microcontainers also revealed a significantly greater stabilising effect of the 174μm microcontainers (p-value of 0.0061).Surprisingly, for microcontainers with an inner diameter of 73μm, no stability improvement was found when compared to amorphous bulk indomethacin. It was observed that the amorphous indomethacin within these containers converted to the α-form of indomethacin (a metastable polymorph) which was unexpected at the storage conditions at 30°C and 23% RH.

KW - Indomethacin

KW - Amorphous

KW - Confinement

KW - Physical stability

KW - Raman microscopy

U2 - 10.1016/j.ejpb.2012.03.017

DO - 10.1016/j.ejpb.2012.03.017

JO - European Journal of Pharmaceutics and Biopharmaceutics

JF - European Journal of Pharmaceutics and Biopharmaceutics

SN - 0939-6411

IS - 2

VL - 81

SP - 418

EP - 425

ER -