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An approach is described for spectrally parallel hyperspectral mid-infrared imaging with spatial resolution dictated by fluorescence imaging. Quantum cascade laser (QCL)-based dual-comb mid-infrared spectroscopy enables the acquisition of infrared spectra at high speed (<1 millisecond) through the generation of optical beat patterns and radio-frequency detection. The high-speed nature of the spectral acquisition is shown to support spectral mapping in microscopy measurements. Direct detection of the transmitted infrared beam yields high signal-to-noise spectral information, but long infrared wavelengths impose low diffraction-limited spatial resolution. The use of fluorescence detected photothermal infrared (F-PTIR) imaging provides high spatial resolution tied directly to the integrated IR absorption. Computational imaging using a multi-agent consensus equilibrium (MACE) approach combines the high spatial resolution of F-PTIR and the high spectral information of dual-comb infrared transmission in a single optimized equilibrium hyperspectral data cube. 

A statistical model enables auto-calibration of second harmonic generation (SHG) images for quantifying trace crystallinity within amorphous solid dispersions (ASDs) over a wide dynamic range of crystallinity. In this paper, we demonstrate particle-counting approaches for quantifying trace crystallinity, combined with analytical expressions correcting for particle overlap bias in higher crystallinity regimes to extend the continuous dynamic range of standard particle-counting algorithms through to the signal averaging regime. The reliability of the values recovered by these expressions was demonstrated with simulated data as well as experimental data obtained for an amorphous solid dispersion formulation containing evacetrapib, an Eli Lilly and Company compound. Since particle counting independently recovers the crystalline volume and the SHG intensity, the average SHG intensity per unit volume can be used as an internal calibrant for quantifying crystallinity at higher volume fractions, for which particle counting is no longer applicable.