Process optimization in pharmaceutical hot-melt extrusion : real-time volatile detection via SIFT-MS combined with multivariate analysis

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Smith, Aaron D. and Bordos, Ecaterina and Devlin, Michael and Hastie, Colin and Perkins, Mark J. and Langford, Vaughan S. and Florence, Alastair J. and Robertson, John (2026) Process optimization in pharmaceutical hot-melt extrusion : real-time volatile detection via SIFT-MS combined with multivariate analysis. International Journal of Pharmaceutics, 691. 126623. ISSN 1873-3476 (https://doi.org/10.1016/j.ijpharm.2026.126623)

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Abstract

Establishing robust processing windows for pharmaceutical polymers during hot-melt extrusion (HME) remains challenging, as conventional thermal analyses reveal little about early chemical change. Here, selected-ion-flow-tube-mass-spectrometry (SIFT-MS) combined with principal component analysis (PCA) was used to characterise real-time volatile evolution under both thermogravimetric (TGA) and extrusion conditions. Centroid-distance mapping and PCA loadings revealed distinct transitions, providing a data-driven means of defining the onset of significant chemical change. Across four representative polymers (Soluplus®, Affinisol™15LV, Kollidon® VA64, and Plasdone™ S630 Ultra), each exhibited changes in volatile composition that marked the onset of temperature-driven chemical evolution. Soluplus® and Plasdone™ S630 Ultra remained stable up to ≈190 °C with optimum extrusion ranges of 150–170 °C. Kollidon® VA64 showed earlier volatile emergence near 180 °C, defining a 160–180 °C window, while Affinisol™15LV, the most viscous system, degraded above 190–200 °C, narrowing its range to 170–185 °C. A brief rheological assessment supported these chemically defined limits, confirming that changes in volatile composition coincide with softening behaviour. Overall, SIFT-MS detected subtle, low-level volatile changes that emerge well before conventional thermal indicators, enabling rapid, non-destructive definition of polymer-specific extrusion windows and enhancing process understanding in amorphous solid dispersion manufacture. Through this analysis we were able to provide a narrower processing range than those defined by their respective manufacturers.

ORCID iDs

Smith, Aaron D., Bordos, Ecaterina ORCID logoORCID: https://orcid.org/0009-0002-2928-1742, Devlin, Michael, Hastie, Colin, Perkins, Mark J., Langford, Vaughan S., Florence, Alastair J. ORCID logoORCID: https://orcid.org/0000-0002-9706-8364 and Robertson, John ORCID logoORCID: https://orcid.org/0000-0002-2191-1319;
CORE (COnnecting REpositories)