Probing the interplay between drug saturation, processing temperature and microstructure of amorphous solid...

The impact of drug saturation and processing regime on the microstructure of amorphous solid dispersions (ASDs) produced by hot-melt extrusion (HME) has been investigated. By exploring various combinations of drug loadings and processing temperatures, a range of drug saturation points were obtained by HME. The process was monitored with an in-line low-frequency Raman probe to construct the respective solubility phase diagram (i.e., solubility of crystalline drug in molten/soften polymer). The resulting ASDs were analysed with synchrotron X-ray phase-contrast micro computed tomography (Sync-XPC-μCT) in conjunction with a tailored image segmentation strategy to extract quantitative and qualitative descriptors. Despite minimal elemental variability between the drug (paracetamol) and the polymer (HPMC), Sync-XPC-μCT provided sufficient contrast to identify multiple structural domains, including drug-rich crystalline clusters, impurities, polymer-related heterogeneities and voids/pores. Supersaturated ASDs (> 20 wt% drug loading) displayed higher structural complexity and showed a plethora of highly defective API-rich crystalline domains upon ageing, which were absent in the undersaturated ASDs. Beyond its impact on the API physical state, the HME processing regime influenced the degree of homogeneity within the polymer fraction, as well as total porosity, size, shape and pore connectivity. By correlating with fundamental API-polymer solubility data, this study offers additional insight into the dynamics of the drug's solubilisation process during extrusion and the subsequent formation of microstructures within the ASD system, which have potential implications on product performance and stability.