Photothermal modulation of multi-photon excited UV autofluorescence is shown to enable label-free mid-infrared spectroscopic imaging with spatial resolution dictated by fluorescence microscopy. One of the main reasons for product recall of solid dosage forms is the lack of content uniformity. 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. In this presentation, fluorescence-detected photothermal mid-infrared (F-PTIR) spectroscopy is proposed for aiding in quantifying content uniformity within pharmaceutical materials.  Notably, a large number of active pharmaceutical ingredients (APIs) are two-photon excited UV-fluorescence (TPE-UVF) active. Label-free autofluorescence-detected photothermal mid-IR (AF-PTIR) microscopy is evaluated as a complement to existing methods for testing the distribution of active pharmaceutical ingredients (APIs) in a mixture containing representative pharmaceutical excipients. 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. Using a custom quantum cascade laser array source allows Boolean patterning of wavelengths for multiplexed spectral detection. 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. 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. The figures of merit for AF-PTIR in pharmaceutical materials characterization will be critically assessed.

Label-free autofluorescence-detected mid-IR photothermal microscopy of pharmaceutical materials

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ACS Fall 2022

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