The influence of drug loading on dissolution behaviours and stability of surfactant-containing amorphous solid dispersions

Abstract

This study explores the impact of drug loading (DL) on the physical stability, dissolution performance, and micellisation behaviour of binary and ternary amorphous solid dispersions (ASDs) of lumefantrine (LUM), a poorly soluble antimalarial drug.

Based on preliminary evaluations, Soluplus® was chosen as the polymer for its excellent solubility enhancement and amorphous stabilisation of LUM, while Kolliphor® RH40 was employed as a surfactant additive due to its synergistic ability to improve solubility and sustain supersaturation with Soluplus®. Binary ASDs (BASDs) and ternary ASDs (TASDs) were produced via hot-melt extrusion (HME) across a DL range of 10–50%. P-XRD and DSC provided qualitative and quantitative insight into DL-dependent amorphisation loss, showing that TASDs exhibited significantly lower T_gs and poorer physical stability than BASDs, with the inferiority amplified at increased DL.

In general, pH-triggered dissolution was seen to deteriorate with increasing DL in both the binary and ternary systems. TASDs outperformed BASDs at low DL (≤20%); however, TASDs were more sensitive to the increase in DL, showing a markedly sharper decline in dissolution at DL ≥ 30%, which resulted in lower drug release relative to their BASD counterparts at higher DLs. At 40% and 50% DL, TASDs even underperformed their corresponding physical mixtures. Dynamic light scattering (DLS) analysis of micelles formed during dissolution revealed that ASDs with higher DLs generated larger and less uniform micelle systems, which correlated with reduced release performance.

Noticeably, the addition of RH40 may disturb Soluplus®-driven micellisation by forming small aggregates, potentially undermining its solubilisation efficiency. Overall, these findings highlight a delicate, DL-dependent balance between the addition of surfactant and formulation robustness, suggesting the need for caution when operating near a potential critical DL, particularly in surfactant-containing ASD systems for high-dose, poorly soluble drugs.

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Materials

LUM (99% purity) was purchased from Kemprotec (Carnforth, UK). Polyvinyl pyrrolidone K30 (PVP K30, Mw 54,000–55,000 g/mol), Polyvinyl pyrrolidone vinyl acetate (PVPVA64, Mw 45,000–70,000 g/mol), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®, 118,000 g/mol), macrogolglycerol ricinoleate (Kolliphor® ELP), macrogolglycerol hydroxystearate (Kolliphor® RH40), poloxamer 407 (Kolliphor® P407), Polysorbate 80 (Kolliphor® PS80) and sodium lauryl sulfate.

Dijia Liu, Shu Li, David S. Jones, Gavin P. Andrews, The influence of drug loading on dissolution behaviours and stability of surfactant-containing amorphous solid dispersions, International Journal of Pharmaceutics, 2026, 126673, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2026.126673.

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