Nanometer-scale residual crystals in a hot melt extruded amorphous solid dispersion: characterization by transmission electron microscopy

Common characterization techniques used to detect crystallinity in amorphous solid dispersions (ASD) typically have detection or quantification limits on the order of 1%. Herein, an amorphous solid dispersion of indomethacin and polyvinylpyrrolidone/vinyl acetate copolymer produced by hot melt extrusion was determined to be amorphous by powder X-ray diffraction and differential scanning calorimetry. However, through the use of transmission electron microscopy, residual crystals of two populations were identified: single crystals mid-dissolution (<100 nm) and nanocrystalline domains of 5–10 nm in size. Both domain types were observed to contain a high defect density. Polarized light microscopy and scanning electron microscopy techniques supplement these findings by corroborating crystallinity. The use of high resolution analytical techniques to identify and characterize residual crystallinity is considered an important first step to understand the significance of these residual crystalline populations to ASD performance attributes.