Second harmonic generation, multi-photon excited fluorescence, and fluorescence-detected photothermal mid-infrared (F-PTIR) spectroscopic microscopy combine to inform the design of amorphous solid dispersions (ASDs). ASDs, in which an active pharmaceutical ingredient (API) is entrained within a soluble polymer matrix, are increasingly used to provide high bioavailability of APIs with low aqueous solubility. However, ASDs tend to be metastable structures, in which spontaneous crystallization and/or amorphous phase separation have the potential to dramatically and negatively impact dissolution kinetics. A combination of new and established nonlinear chemical imaging methods collectively provide highly complementary information on structure and composition within ASDs. Specifically, we will describe modeling of crystal formation within ASD materials as probed by second harmonic generation imaging over a large dynamic range. Studies of crystallinity by SHG are complemented by a combination of multi-photon excited fluorescence with patterned illumination and F-PTIR to probe composition and molecular mobility within amorphous phase-separated domains in ASDs following water vapor exposure. These collective results highlight the utility of nonlinear optical imaging approaches for predictive modeling of stability and bioavailability in pharmaceutical formulations.

Informing pharmaceutical materials design through hyperspectral and nonlinear opticl microscopy

ACS Fall 2021

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