Many analytical methods can be used to characterize active pharmaceutical ingredients (APIs), such as X-ray diffraction (XRD), Raman, IR-spectroscopy, solid state NMR, differential scanning calorimetry, transmission and scanning electron microscopy. However, these methods typically exhibit detection limits above 1%, which can complicate analysis of materials with low crystal loadings.Second harmonic generation (SHG) microscopy in combination with two-photon excited ultraviolet fluorescence (TPE-UVF) is an attractive alternative for the determination of percent crystallinity of a sample. In previous studies, calibration curves were prepared to quantitatively assess the viability of SHG-based crystallinity detection, and were found to be in good agreement with typical techniques such as powder X-ray diffraction. However, SHG provides little direct structural information about the crystal lattice/composition.Limits of detection for benchtop X-ray diffractometers are on the order of a few percent. However, the incorporation of a nonlinear optical instrument, combining SHG, TPE-UVF, with a synchrotron X-ray source, allows for the potential to substantially decrease XRD limits of detection.  In preliminary work, pharmaceutical samples with a 0.01% w/w API loading were examined, resulting in strong agreement with SHG (a) and X-ray raster scanned diffraction (b). The spot showing greatest diffraction suggests the presence of crystalline material (c), with enlarged region of interest (d). Combining mini-beam collimation of the synchrotron beam with area detection of the diffracted X-rays has the potential to identify crystal forms at ppm or ppb levels.

Towards powder X-ray diffraction with PPM limits of detection for active pharmaceutical ingredients with integrated nonlinear optical instrumentation

246th National Meeting (2013)

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