We demonstrate instrumentation and methods to enable fluorescence-detected photothermal infrared (F-PTIR) microscopy and then demonstrate the utility of F-PTIR to characterize the composition within phase-separated domains of model amorphous solid dispersions (ASDs) induced by water sorption. In F-PTIR, temperature-dependent changes in fluorescence quantum efficiency are shown to sensitively report on highly localized absorption of mid-infrared radiation. The spatial resolution with which infrared spectroscopy can be performed is dictated by fluorescence microscopy, rather than the infrared wavelength. Intrinsic ultraviolet autofluorescence of tryptophan and protein microparticles enabled label-free F-PTIR microscopy. Following proof of concept F-PTIR demonstration on model systems of polyethylene glycol (PEG) and silica gel, F-PTIR enabled the characterization of chemical composition within inhomogeneous ritonavir/polyvinylpyrrolidone-vinyl acetate (PVPVA) amorphous dispersions. Phase separation is implicated in the observation of critical behaviors in ASD dissolution kinetics, with the results of F-PTIR supporting the formation of phase-separated drug-rich domains upon water sorption in spin-cast films.

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Label-free autofluorescence-detected photothermal mid-IR (AF-PTIR) microscopy is demonstrated experimentally and applied to test the distribution of active pharmaceutical ingredients (APIs) in a mixture containing representative pharmaceutical excipients. Two-photon excited UV-fluorescence (TPE-UVF) supports autofluorescence of native aromatic moieties using visible-light optics. Thermal modulation of the fluorescence quantum yield serves to report on infrared absorption, enabling infrared spectroscopy in the fingerprint region with a spatial resolution dictated by fluorescence. AF-PTIR provides high selectivity and sensitivity in image contrast for aromatic APIs, complementing broadly applicable optical photothermal IR (O-PTIR) microscopy based on photothermal modulation of refractive index/scattering. Mapping the API distribution is critical in designing processes for powdered dosage form manufacturing, with high spatial variance potentially producing variability in both delivered dosage and product efficacy. The ubiquity of aromatic moieties within API candidates suggests the viability of AF-PTIR in combination with O-PTIR to improve the confidence of chemical classification in spatially heterogeneous dosage forms.

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