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oai:figshare.com:article/32805443 2026-10-01T16:16:06Z portal_1172 item_type_8 month_year_10_2026

Drug enabling strategies for oral delivery of a poorly soluble antimalarial: amorphous solid dispersions and self-emulsifying systems via hot-melt extrusion Dijia Liu (3926588) PUREID: 674211859 Amorphous solid dispersions (ASDs)) self-emulsifying drug delivery systems (SEDDS)) hot-melt extrusion (HME) lumefantrine artemether malaria solubility improvement in vitro dissolution micellisation pH-responsive drug release drug loading This thesis addresses a central pharmaceutical barrier in artemisinin-based combination therapy (ACT) for malaria. Lumefantrine (LUM), a lipophilic component co-administered with artemether (ART), exhibits extremely poor aqueous solubility and suboptimal oral bioavailability, undermining therapeutic reliability. Two enabling strategies, amorphous solid dispersions (ASDs) and self-emulsifying drug delivery systems (SEDDS), were advanced using hot-melt extrusion (HME) as the manufacturing platform.<br><br>LUM ASDs were systematically investigated. Binary (LUM–Soluplus®) and ternary (LUM–Soluplus®–Kolliphor® RH40) ASDs were prepared at 10–50% drug loadings (DL) and assessed for stability, dissolution, and micellar properties. Surfactant incorporation (RH40) proved detrimental to amorphisation and stability across all DLs. While ternary ASDs improved dissolution at 10% DL, they exhibited reduced release at ≥30% DL, underperforming even physical mixtures at 40–50% DL. This impairment is linked to disruption of Soluplus®-mediated micellisation by RH40, an effect that intensified with increasing RH40-to-Soluplus® ratio.<br><br>A solid SEDDS design integrating ASD principles was then developed. A two-step HME process, amorphisation followed by lipid incorporation, enabled manufacture of solid SEDDS with >40% DL. Within these systems, LUM reverted to a crystalline state, mitigating the risks associated with amorphous instability. Ternary ASD-derived SEDDS exhibited distinctive pH-responsive dissolution: an initial burst release with precipitation in acidic medium, followed by pronounced re-solubilisation upon neutralisation. The transient formation of an amorphous intermediate during processing contributed to matrix homogenisation and enhanced pH-triggered solubilisation. Furthermore, this secondary solubilisation appeared to be linked to pH-triggered colloidal reorganisation. The platform was successfully extended to ART–LUM co-loaded SEDDS pellets, which preserved pH-responsive release and delivered superior dissolution of both actives compared to single-loaded SEDDS and a marketed reference, demonstrating its translational potential.<br><br><i>Thesis is embargoed until 31 July 2031.</i><br> 2026-10-01T16:16:06Z Text Thesis 10.17034/32805443.v1 https://figshare.com/articles/thesis/Drug_enabling_strategies_for_oral_delivery_of_a_poorly_soluble_antimalarial_amorphous_solid_dispersions_and_self-emulsifying_systems_via_hot-melt_extrusion/32805443 All Rights Reserved Open Access after 2031-07-31