Spatial confinement can lead to increased stability of amorphous indomethacin

Research output: Contribution to journalJournal articlepeer-review

Standard

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 : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, Vol. 81, No. 2, 2012, p. 418-25.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Nielsen, LH, Keller, SS, Gordon, KC, Boisen, A, Rades, T & Müllertz, A 2012, 'Spatial confinement can lead to increased stability of amorphous indomethacin', European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, vol. 81, no. 2, pp. 418-25. https://doi.org/10.1016/j.ejpb.2012.03.017

APA

Nielsen, L. H., Keller, S. S., Gordon, K. C., Boisen, A., Rades, T., & Müllertz, A. (2012). Spatial confinement can lead to increased stability of amorphous indomethacin. European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 81(2), 418-25. https://doi.org/10.1016/j.ejpb.2012.03.017

Vancouver

Nielsen LH, Keller SS, Gordon KC, Boisen A, Rades T, Müllertz A. Spatial confinement can lead to increased stability of amorphous indomethacin. European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V. 2012;81(2):418-25. https://doi.org/10.1016/j.ejpb.2012.03.017

Author

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 : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V. 2012 ; Vol. 81, No. 2. pp. 418-25.

Bibtex

@article{04978e4806554f48b810b617f9049e50,
title = "Spatial confinement can lead to increased stability of amorphous indomethacin",
abstract = "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 ¿-indomethacin, respectively, followed by quench-cooling. Microcontainers of three different sizes (diameters of 73 µm, 174 µm and 223 µm) 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 30 days 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 174 µm microcontainers, 29.0 ± 2.6% of the amorphous indomethacin crystallised to the stable ¿-form over a period of 30 days, whilst 38.3 ± 1.5% of the amorphous indomethacin crystallised in the 223 µm microcontainers. Both these values were significantly different from that observed in the amorphous bulk indomethacin, where 51.0% crystallised to the ¿-form after 30 days. Comparing the 174 and 223 µm 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 73 µm, no stability improvement was found when compared to amorphous bulk indomethacin. It was observed that the amorphous indomethacin within these containers converted to the a-form of indomethacin (a metastable polymorph) which was unexpected at the storage conditions at 30 °C and 23% RH.",
author = "Nielsen, {Line Hagner} and Keller, {Stephan Sylvest} and Gordon, {Keith C} and Anja Boisen and Thomas Rades and Anette M{\"u}llertz",
note = "Copyright {\textcopyright} 2012 Elsevier B.V. All rights reserved.",
year = "2012",
doi = "10.1016/j.ejpb.2012.03.017",
language = "English",
volume = "81",
pages = "418--25",
journal = "European Journal of Pharmaceutics and Biopharmaceutics",
issn = "0939-6411",
publisher = "Elsevier",
number = "2",

}

RIS

TY - JOUR

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

AU - Nielsen, Line Hagner

AU - Keller, Stephan Sylvest

AU - Gordon, Keith C

AU - Boisen, Anja

AU - Rades, Thomas

AU - Müllertz, Anette

N1 - Copyright © 2012 Elsevier B.V. All rights reserved.

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 ¿-indomethacin, respectively, followed by quench-cooling. Microcontainers of three different sizes (diameters of 73 µm, 174 µm and 223 µm) 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 30 days 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 174 µm microcontainers, 29.0 ± 2.6% of the amorphous indomethacin crystallised to the stable ¿-form over a period of 30 days, whilst 38.3 ± 1.5% of the amorphous indomethacin crystallised in the 223 µm microcontainers. Both these values were significantly different from that observed in the amorphous bulk indomethacin, where 51.0% crystallised to the ¿-form after 30 days. Comparing the 174 and 223 µm 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 73 µm, no stability improvement was found when compared to amorphous bulk indomethacin. It was observed that the amorphous indomethacin within these containers converted to the a-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 ¿-indomethacin, respectively, followed by quench-cooling. Microcontainers of three different sizes (diameters of 73 µm, 174 µm and 223 µm) 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 30 days 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 174 µm microcontainers, 29.0 ± 2.6% of the amorphous indomethacin crystallised to the stable ¿-form over a period of 30 days, whilst 38.3 ± 1.5% of the amorphous indomethacin crystallised in the 223 µm microcontainers. Both these values were significantly different from that observed in the amorphous bulk indomethacin, where 51.0% crystallised to the ¿-form after 30 days. Comparing the 174 and 223 µm 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 73 µm, no stability improvement was found when compared to amorphous bulk indomethacin. It was observed that the amorphous indomethacin within these containers converted to the a-form of indomethacin (a metastable polymorph) which was unexpected at the storage conditions at 30 °C and 23% RH.

U2 - 10.1016/j.ejpb.2012.03.017

DO - 10.1016/j.ejpb.2012.03.017

M3 - Journal article

C2 - 22521331

VL - 81

SP - 418

EP - 425

JO - European Journal of Pharmaceutics and Biopharmaceutics

JF - European Journal of Pharmaceutics and Biopharmaceutics

SN - 0939-6411

IS - 2

ER -

ID: 40331697