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Indomethacin: New Polymorphs of an Old Drug
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