Indomethacin: New polymorphs of an old drug

Sachin A Surwase; Johan Peter Bøtker; Dorothy Saville; Ben J Boyd; Keith C Gordon; Leena Peltonen; Clare J Strachan

doi:10.1021/mp400299a

Indomethacin: New polymorphs of an old drug

Sachin A Surwase, Johan Peter Bøtker, Dorothy Saville, Ben J Boyd, Keith C Gordon, Leena Peltonen, Clare J Strachan

80 Citations (Scopus)

Abstract

This study reports the appearance and characterization of multiple new polymorphic forms of indomethacin. Considering the interest in amorphous suspensions for toxicology studies of poorly water-soluble drugs, we sought to investigate the crystallization behavior of amorphous indomethacin in aqueous suspension. Specifically, the effect of pH and temperature on crystallization behavior was studied. Quench cooled amorphous powder was added to buffered media at different pH values (1.2, 4.5, and 6.8) at 5 and 25°C. Both the solid and the solution were analyzed at different time points up to 24 h. Attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy (with principal component analysis) was used to study solid-phase transformations and ultraviolet (UV) spectroscopy used to probe solution concentration. The crystallization onset time decreased and rate of crystallization increased with increasing pH and temperature. Diverse polymorphic forms were observed, with three new forms being identified; these were named ε, ζ, and η. At 25°C, the amorphous form recrystallized directly to the α form, except at pH 6.8, where it initially converted briefly into the ε form. At 5°C, all three new polymorphic forms were observed sequentially in the order ε, ζ, and then η, with the number of these forms observed increasing sequentially with decreasing pH. The three new forms exhibited distinct X-ray powder diffraction (XPRD), differential scanning calorimetry (DSC), and FTIR and Raman spectroscopy profiles. The solution concentration profiles suggest that the relative physical stabilities of the polymorphs at 5°C from lowest to highest is ε < ζ < η < α. The appearance of new polymorphs in this study suggests that amorphous suspensions are worth considering when performing polymorphic screening studies.

Original language	English
Journal	Molecular Pharmaceutics
Volume	10
Issue number	12
Pages (from-to)	4472-4480
ISSN	1543-8384
DOIs	https://doi.org/10.1021/mp400299a
Publication status	Published - 2 Dec 2013

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10.1021/mp400299a

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title = "Indomethacin: New polymorphs of an old drug",

abstract = "This study reports the appearance and characterization of multiple new polymorphic forms of indomethacin. Considering the interest in amorphous suspensions for toxicology studies of poorly water-soluble drugs, we sought to investigate the crystallization behavior of amorphous indomethacin in aqueous suspension. Specifically, the effect of pH and temperature on crystallization behavior was studied. Quench cooled amorphous powder was added to buffered media at different pH values (1.2, 4.5, and 6.8) at 5 and 25°C. Both the solid and the solution were analyzed at different time points up to 24 h. Attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy (with principal component analysis) was used to study solid-phase transformations and ultraviolet (UV) spectroscopy used to probe solution concentration. The crystallization onset time decreased and rate of crystallization increased with increasing pH and temperature. Diverse polymorphic forms were observed, with three new forms being identified; these were named ε, ζ, and η. At 25°C, the amorphous form recrystallized directly to the α form, except at pH 6.8, where it initially converted briefly into the ε form. At 5°C, all three new polymorphic forms were observed sequentially in the order ε, ζ, and then η, with the number of these forms observed increasing sequentially with decreasing pH. The three new forms exhibited distinct X-ray powder diffraction (XPRD), differential scanning calorimetry (DSC), and FTIR and Raman spectroscopy profiles. The solution concentration profiles suggest that the relative physical stabilities of the polymorphs at 5°C from lowest to highest is ε < ζ < η < α. The appearance of new polymorphs in this study suggests that amorphous suspensions are worth considering when performing polymorphic screening studies.",

author = "Surwase, {Sachin A} and B{\o}tker, {Johan Peter} and Dorothy Saville and Boyd, {Ben J} and Gordon, {Keith C} and Leena Peltonen and Strachan, {Clare J}",

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T2 - New polymorphs of an old drug

AU - Surwase, Sachin A

AU - Bøtker, Johan Peter

AU - Saville, Dorothy

AU - Boyd, Ben J

AU - Gordon, Keith C

AU - Peltonen, Leena

AU - Strachan, Clare J

PY - 2013/12/2

Y1 - 2013/12/2

N2 - This study reports the appearance and characterization of multiple new polymorphic forms of indomethacin. Considering the interest in amorphous suspensions for toxicology studies of poorly water-soluble drugs, we sought to investigate the crystallization behavior of amorphous indomethacin in aqueous suspension. Specifically, the effect of pH and temperature on crystallization behavior was studied. Quench cooled amorphous powder was added to buffered media at different pH values (1.2, 4.5, and 6.8) at 5 and 25°C. Both the solid and the solution were analyzed at different time points up to 24 h. Attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy (with principal component analysis) was used to study solid-phase transformations and ultraviolet (UV) spectroscopy used to probe solution concentration. The crystallization onset time decreased and rate of crystallization increased with increasing pH and temperature. Diverse polymorphic forms were observed, with three new forms being identified; these were named ε, ζ, and η. At 25°C, the amorphous form recrystallized directly to the α form, except at pH 6.8, where it initially converted briefly into the ε form. At 5°C, all three new polymorphic forms were observed sequentially in the order ε, ζ, and then η, with the number of these forms observed increasing sequentially with decreasing pH. The three new forms exhibited distinct X-ray powder diffraction (XPRD), differential scanning calorimetry (DSC), and FTIR and Raman spectroscopy profiles. The solution concentration profiles suggest that the relative physical stabilities of the polymorphs at 5°C from lowest to highest is ε < ζ < η < α. The appearance of new polymorphs in this study suggests that amorphous suspensions are worth considering when performing polymorphic screening studies.

AB - This study reports the appearance and characterization of multiple new polymorphic forms of indomethacin. Considering the interest in amorphous suspensions for toxicology studies of poorly water-soluble drugs, we sought to investigate the crystallization behavior of amorphous indomethacin in aqueous suspension. Specifically, the effect of pH and temperature on crystallization behavior was studied. Quench cooled amorphous powder was added to buffered media at different pH values (1.2, 4.5, and 6.8) at 5 and 25°C. Both the solid and the solution were analyzed at different time points up to 24 h. Attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy (with principal component analysis) was used to study solid-phase transformations and ultraviolet (UV) spectroscopy used to probe solution concentration. The crystallization onset time decreased and rate of crystallization increased with increasing pH and temperature. Diverse polymorphic forms were observed, with three new forms being identified; these were named ε, ζ, and η. At 25°C, the amorphous form recrystallized directly to the α form, except at pH 6.8, where it initially converted briefly into the ε form. At 5°C, all three new polymorphic forms were observed sequentially in the order ε, ζ, and then η, with the number of these forms observed increasing sequentially with decreasing pH. The three new forms exhibited distinct X-ray powder diffraction (XPRD), differential scanning calorimetry (DSC), and FTIR and Raman spectroscopy profiles. The solution concentration profiles suggest that the relative physical stabilities of the polymorphs at 5°C from lowest to highest is ε < ζ < η < α. The appearance of new polymorphs in this study suggests that amorphous suspensions are worth considering when performing polymorphic screening studies.

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DO - 10.1021/mp400299a

M3 - Journal article

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SN - 1543-8384

VL - 10

SP - 4472

EP - 4480

JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

IS - 12

ER -

Indomethacin: New polymorphs of an old drug

Abstract

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