Paladino, E; Doerr, F J S; Bordos, E; Onyemelukwe, I I; Lamprou, D A; Florence, A J; Gilmore, I S; Halbert, G W (2022) High spatial resolution ToF-SIMS imaging and image analysis strategies to monitor and quantify early phase separation in amorphous solid dispersions. International Journal of Pharmaceutics, 628. 122191

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Abstract

Amorphous solid dispersions (ASDs) are formulations with enhanced drug solubility and dissolution rate compared to the crystalline counterparts. However, they are characterised by an inherent thermodynamic instability leading to amorphous phase separation and drug re-crystallisation. These phenomena are faster at the product’s surface. This study investigates the use of high-resolution time of flight-secondary ion mass spectrometry (ToF-SIMS) imaging and image-analysis for early detection, monitoring and quantification of surface amorphous phase separation in ASDs. Its capabilities were 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% 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 API-rich clusters already in the first days of storage. 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 surface phase separation and re-crystallisation. In this study, it outperformed commonly applied techniques to detect crystalline material such as XRPD.

Item Type:	Article
Keywords:	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)
Subjects:	Nanoscience > Surface and Nanoanalysis
Divisions:	Chemical & Biological Sciences
Identification number/DOI:	10.1016/j.ijpharm.2022.122191
Last Modified:	31 Jan 2024 14:38
URI:	https://eprintspublications.npl.co.uk/id/eprint/9915