Fluorescence-detected mid-infrared photothermal microscopy (F-PTIR) is demonstrated experimentally and applied to characterize composition within phase-separated domains in a model amorphous solid dispersion (ASD). ASDs are formulations composed of molecularly mixed drug and polymer, which are widely used to enhance the dissolution kinetics of many active pharmaceutical ingredients (APIs). However, drug loadings exceeding critical thresholds result in reductions in dissolution rates (Fig. 1, a). We hypothesize that this “dropping off a cliff” phenomenon is due to phase separation of poorly soluble drug-rich domains. To evaluate composition within the phase-separated domains, we developed a new method for infrared spectroscopic microscopy, in which temperature-dependent changes in the fluorescence quantum efficiency served as a local photothermal reporter for absorption of infrared light. Phase-separated domains in spin-coated films of ritonavir/PVPVA/Nile red amorphous dispersion following water vapor exposure exhibit clear enrichment in ritonavir (Fig 1, c and d). The preferential partitioning of ritonavir into phase-separated domains is further supported by the label free TPE-UVF measurements, which demonstrated ritonavir-specific autofluorescence activity in domains structurally similar with those identified as ritonavir-rich by F-PTIR (Fig. 1, d).

Fluorescence-detected photothermal infrared microscopy supports phase separation within ritonavir/copovidone amorphous dispersions

ACS Fall 2021

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