TY - JOUR

T1 - Indomethacin

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

Y1 - 2013/12

N2 - This study reports the appearance and characterization of multiple new polymorphic forms of indomethacin (IND). Considering the interest in amorphous suspensions for toxicology studies of poorly water soluble drugs, we sought to investigate the crystallization behaviour of amorphous IND in aqueous suspension. Specifically, the effect of pH and temperature on crystallization behaviour 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 solution were analyzed at different time points up to 24 h. ATR-FTIR-spectroscopy (with principal component analysis) was used to study solid-phase transformations and 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 XPRD, 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

AB - This study reports the appearance and characterization of multiple new polymorphic forms of indomethacin (IND). Considering the interest in amorphous suspensions for toxicology studies of poorly water soluble drugs, we sought to investigate the crystallization behaviour of amorphous IND in aqueous suspension. Specifically, the effect of pH and temperature on crystallization behaviour 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 solution were analyzed at different time points up to 24 h. ATR-FTIR-spectroscopy (with principal component analysis) was used to study solid-phase transformations and 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 XPRD, 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

U2 - 10.1021/mp400299a

DO - 10.1021/mp400299a

M3 - Journal article

C2 - 24025118

VL - 10

SP - 4472

EP - 4480

JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

SN - 1543-8384

IS - 12

ER -