Second harmonicgeneration (SHG) optical imaging enables rapid identification of �areas ofinterest� for targeted diffraction using a mini-beam synchrotron diffractionsource, with the combined analysis greatly reducing the detection limits inanalysis of trace crystallinity within amorphous formulations.  Reducing the dimensions of the X-ray beam toapproach those of the trace crystal form (~5 mm in diameter)suppresses background scatter, enabling diffraction measurements on pgquantities of crystalline material. Since the SHG measurements can be performedquickly (few seconds per frame), pre-screening by SHG maximizes the use ofprecious beam-time for combined analysis. We describe the integration of abeam-scanning SHG microscope into a synchrotron beamline at Argonne NationalLaboratory. Using this combined system integrating both microscopy with anultrafast laser source and synchrotron XRD in a single-platform instrument,powder peaks with signal to noise exceeding 3000 were obtained for 100 ppmritonavir in hydroxypropylmethylcellulose. In studies of inkjet printed aminoacids, diffraction analysis was performed on ~1 pg of material deposited from asingle inkjet printed dot from ~1 pL of solution. These results suggest thatthis combined approach should enable routine powder XRD of organic crystals inthe low ppm to high ppb range and/or for pg quantities of total crystalline material.

PPM detection limits in powder X-ray diffraction of amorphous pharmaceutical formulations

248th National Meeting (2014)

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