Ultramicroscopy of complex pharmaceutical materials

Transmission electron microscopy (TEM) is a promising tool for the analysis of pharmaceutical therapeutics because it can probe key interfaces, drug distribution, phase type, stability and defects. This work explores parallel beam and focussed probe, scanning (S)TEM for the analysis of four model pharmaceutical compounds. First, and for each compound analysed, the characteristic or critical electron fluence for irradiation-induced fading of an electron diffraction pattern is established. Any further data are acquired within this electron budget to minimize specimen alteration. The results demonstrate that STEM imaging and elemental analysis can provide information on performance parameters such as defect type and concentration, composition, strain, phase transformation pathways and barriers to the release of a drug. Specifically, scanning electron diffraction (SED) and scanning moiré fringe (SMF) methods image the crystal lattice and identify defects in a small molecule drug, furosemide; highlighting that strain in furosemide (001) crystal planes is less than for (010). Scanning electron microscopy (SEM) and STEM lattice imaging with energy-dispersive X-ray spectroscopy (EDX), reveal a decrease in micrometre particle size and loss of shape, surface contamination by silicate nanoparticles, and a lowering of Na+ content on protonation of a development batch of a model K+ cation exchanger, sodium zirconium silicate. SED shows that hydrate formation from theophylline anhydrous form II is solution-mediated, dissolution-re-precipitation phase transformation. TEM and SED show that vacuum and thermal dehydration of theophylline monohydrate begins at particle surfaces with exposed water channels undergoing surface etching (first step), and then, water is removed from deeper in particles via diffusion along water channels (second step), to produce anhydrous form III before thermally induced reconstruction to anhydrous from II. Finally, multi-modal cryogenic (S)TEM of new modality, polymeric nanoparticles imaged in the frozen, hydrated state, reveals a multi-layer particle structure that indicates release of API from the 50 nm cores is through a 9 nm thick, layer of polylactic acid - polyethylene glycol co-polymer.