Hidden Solid-State Transformation of Darunavir in Low-Temperature Hot-Melt-Extruded Granules: Implications for...

Background: Hot-melt extrusion (HME) is a scalable pharmaceutical technology increasingly relevant to flexible manufacturing, including small-batch production, personalized dosage-form development, and potential use in pharmacy compounding. When translated into compounding practice, however, HME introduces a risk that routine quality-control methods available in pharmacies may be insufficient to reliably assess the stability of extrusion-based preparations. Methods: Granules containing 50% (w/w) darunavir were prepared by HME at 70 and 90 °C using a previously developed polymeric premix. Samples were stored for 24 months under ambient conditions. During storage, routine quality attributes were evaluated, including appearance, particle size distribution, loss on drying, disintegration time, content uniformity, and assay. Solid-state changes were investigated using differential scanning calorimetry (DSC) and X-ray diffraction (XRD), with a reference PEG-associated darunavir sample prepared and characterized for comparative analysis. Changes in drug release and darunavir content were assessed by dissolution testing and HPLC analysis, respectively. Results: Granules produced at both extrusion temperatures retained acceptable routine quality attributes throughout the 24-month storage period. No substantial changes were detected by visual inspection, pharmacopoeial tests, or UV assay. However, DSC revealed a new thermal event after storage, while XRD showed the formation of a new crystalline phase. Comparison with the reference PEG-associated sample supported the assignment of this phase as a PEG-associated crystalline phase of darunavir. Importantly, this transformation occurred even though the routine quality attributes evaluated in pharmacy compounding practice remained unchanged. Dissolution profiles differed between samples tested immediately after preparation and after long-term storage, with a more pronounced overall difference for granules produced at 90 °C, whereas HPLC confirmed comparable darunavir content in all investigated samples. Discussion: Our results show that routine compounding quality control can meet conventional acceptance criteria while failing to detect API solid-state changes in the investigated HME-derived system. In the PEG-containing matrix, amorphous darunavir undergoes storage-induced crystallization, forming a PEG-associated crystalline phase consistent with its known affinity for polyol-containing media. Conclusions: Acceptable routine quality attributes do not necessarily reflect the solid-state stability of APIs in HME-based formulations. These results highlight the need for solid-state risk assessment when developing extrusion-based systems intended for pharmacy compounding and other personalized manufacturing models in which routine quality control may not include advanced solid-state characterization.