Parts-per-Million Detection of Trace Crystal Forms Using AF-PTIR Microscopy.

Autofluorescence-detected photothermal mid-infrared (AF-PTIR) microscopy was shown to enable parts-per-million detection of α-indomethacin impurity in γ-indomethacin samples. Subtle differences in the photothermal response of the UV-autofluorescence of two indomethacin crystal polymorphs were used for sub-micron chemical discrimination based on fingerprint region mid-IR spectroscopy. The AF-PTIR assignment was independently confirmed by second harmonic generation (SHG) microscopy, which was shown to reduce the total analysis time by rapidly identifying the suitable fields of view. AF-PTIR microscopy has the potential to assist in the early identification of crystal form impurities in the solid dosage forms development pipeline.