High spatial resolution ToF-SIMS imaging and image analysis strategies to monitor and quantify early phase separation in amorphous solid dispersions

Eleonora Paladino, Frederik J.S. Doerr, Ecaterina Bordos, Iyke I. Onyemelukwe, Dimitrios A. Lamprou, Alastair J. Florence, Ian S. Gilmore, Gavin W. Halbert

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3 Citations (Scopus)
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Amorphous solid dispersions (ASDs) are formulations with enhanced drug solubility and dissolution rate compared to their crystalline counterparts, however, they can be inherently thermodynamically unstable. This can lead to amorphous phase separation and drug re-crystallisation, phenomena that are typically faster and more dominant at the product's surfaces. This study investigates the use of high-resolution time of flight-secondary ion mass spectrometry (ToF-SIMS) imaging as a surface analysis technique combined with image-analysis for the early detection, monitoring and quantification of surface amorphous phase separation in ASDs. Its capabilities are demonstrated for two pharmaceutically relevant ASD systems with distinct re-crystallisation behaviours, prepared using hot melt extrusion (HME) followed by pelletisation or grinding: (1) paracetamol-hydroxypropyl methylcellulose (PCM-HPMC) pellets with drug loadings of 10%–50% w/w and (2) indomethacin-polyvinylpyrrolidone (IND-PVP) ground material with drug loadings of 20%–85% w/w. PCM-HPMC pellets showed intense phase separation, reaching 100% PCM surface coverage within 1–5 months. In direct comparison, IND-PVP HME ground material was more stable with only a moderate formation of isolated IND-rich clusters. Image analysis allowed the reliable detection and quantification of local drug-rich clusters. An Avrami model was applied to determine and compare phase separation kinetics. The combination of chemical sensitivity and high spatial resolution afforded by SIMS was crucial to enable the study of early phase separation and re-crystallisation at the surface. Compared with traditional methods used to detect crystalline material, such as XRPD, we show that ToF-SIMS enabled detection of surface physical instability already at early stages of drug cluster formation in the first days of storage.

Original languageEnglish
Article number122191
Number of pages12
JournalInternational Journal of Pharmaceutics
Early online date30 Sept 2022
Publication statusPublished - 25 Nov 2022


  • chemical imaging
  • time of flight-secondary ion mass spectrometry (ToF-SIMS)
  • pharmaceutical solid products
  • amorphous solid dispersion (ASD)
  • surface physical stability
  • amorphous phase separation
  • surface-enhanced re-crystallisation
  • crystal nucleation
  • crystal growth
  • hot melt extrusion (HME)


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