Characterization of Amorphous Solid Dispersions and Identification of Low Levels of Crystallinity by Transmission Electron Microscopy

Amorphous solid dispersions (ASDs)
are used to increase the solubility
of oral medicines by kinetically stabilizing the more soluble amorphous
phase of an active pharmaceutical ingredient with a suitable amorphous
polymer. Low levels of a crystalline material in an ASD can negatively
impact the desired dissolution properties of the drug. Characterization
techniques such as powder X-ray diffraction (pXRD), differential scanning
calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR)
are often used to detect and measure any crystallinity within ASDs.
These techniques are unable to detect or quantify very low levels
because they have limits of detection typically in the order of 1–5%.
Herein, an ASD of felodipine (FEL) and polyvinylpyrrolidone/vinyl
acetate copolymer (PVP/VA) prepared via a hot melt extrusion (HME)
in a mass ratio of 30:70 was characterized using a range of techniques.
No signs of residual crystallinity were found by pXRD, DSC, or FTIR.
However, transmission electron microscopy (TEM) did identify two areas
containing crystals at the edges of milled particles from a total
of 55 examined. Both crystalline areas contained Cl Kα X-ray
peaks when measured by energy-dispersive X-ray spectroscopy, confirming
the presence of FEL (due to the presence of Cl atoms in FEL and not
in PVP/VA). Further analysis was carried out by TEM using conical
dark field (DF) imaging of a HME ASD of 50:50 FEL-PVP/VA to provide
insights into the recrystallization process that occurs at the edges
of particles during accelerated ageing conditions in an atmosphere
of 75% relative humidity. Multiple metastable polymorphs of recrystallized
FEL could be identified by selected area electron diffraction (SAED),
predominately form II and the more stable form I. Conical DF imaging
was also successful in spatially resolving and sizing crystals. This
work highlights the potential for TEM-based techniques to improve
the limit of detection of crystallinity in ASDs, while also providing
insights into transformation pathways by identifying the location,
size, and form of any crystallization that might occur on storage.
This opens up the possibility of providing an enhanced understanding
of a drug product’s stability and performance.