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Updated: Jun 17, 2026
Synthesis of Cyclic Polymers and Characterization of Their Diffusive Motion in the Melt State at the Single Molecule Level
Published on: September 26, 2016
Analyzing Spatial Variations in Molecular Mobility in Hydrated Amorphous Drug-Polymer Blends Using Fourier Transform
Michelle L Cousineau1, Maura M Wimsatt2, Garth J Simpson2
1Department of Industrial and Molecular Pharmaceutics, Purdue University, West Lafayette, Indiana 47907, United States.
Abstract:
Amorphous solid dispersions (ASDs) can enhance oral bioavailability of poorly soluble drugs but often undergo hydration-induced phase separation, which complicates drug release and undermines physical stability. Here we integrate diffractive-optics-enabled Fourier transform fluorescence recovery after photobleaching (FT-FRAP) with image segmentation in a controlled "glass-sandwich" hydration platform to quantify phase-resolved molecular mobility within hydrating ibuprofen-copovidone compacts. Release studies distinguished a rapidly releasing 10% w/w drug loading (DL) ibuprofen ASD from a poorly releasing 15% DL ASD. Confocal fluorescence microscopy revealed discrete, dispersed hydrophobic domains following hydration at 10% DL versus a persistent, connected drug-rich barrier that formed at the ASD-buffer interface for the 15% DL ASD. Dynamic light scattering studies of solutions following release from 10% DL ASD compacts demonstrated the presence of nanodroplets of 520 ± 8 nm, consistent with observations from microscopy studies. FT-FRAP with segmentation (rhodamine 6G probe) resolved domain-specific transport kinetics through elucidation of regional values of the probe diffusivity (D): low-hydration ASD region (Dtrans < 0.017 μm2·s-1; Drot = 0.21 ± 0.01 radians2·s-1), ASD gel (Dtrans = 0.91 ± 0.07 μm2·s-1), aqueous regions (Dtrans > 120 μm2·s-1), and amorphous ibuprofen-rich phase (Dtrans = 0.082 ± 0.002 μm2·s-1). Stokes-Einstein estimates translated these values into local viscosities spanning ∼0.41 Pa·s (gel), 4.5 Pa·s (ibuprofen-rich), and 22 Pa·s (low-hydration ASD), highlighting pronounced microheterogeneity within the hydrated ASD matrix. Together, these results provide a quantitative, spatially explicit link between drug loading, phase morphology, local mobility, and macroscopic release, and establish segmented FT-FRAP as a practical tool for diagnosing failure mechanisms and guiding formulation of high-loading ASDs.
