Poor aqueous solubility predisposes an increasing number of active pharmaceutical ingredients (APIs) to low bioavailability and suboptimal clinical performance when administered orally. Lumefantrine (LUM) is a notable example, exhibiting a crystalline solubility of only 2.6 ng/mL in fasted-state simulated intestinal fluid (FaSSIF) (Jain et al., 2017). It is weakly basic (pKa of the tertiary amine = 8.73) (Amin et al., 2013) and highly hydrophobic (log P = 8.34) (Wahajuddin et al., 2014). The therapeutic efficacy of LUM often depends on co-administration with a high-fat meal (e.g., a glass of milk) and a high-dose regimen (24 tablets over three days for adults; six tablets for infants weighing 5–15 kg, with each tablet containing 120 mg of LUM) (Novartis, 2019). This reliance on food intake and high dosing contributes to significant interindividual variability in pharmacokinetic profiles, increasing the risk of poor patient compliance and treatment failure (Lohy Das et al., 2018). Moreover, as LUM is co-formulated with artemether in first-line artemisinin-based combination therapies, a portion of the formulation space must be reserved for the partner drug, further intensifying the challenge of accommodating high drug loads within a limited dosage volume.

Amorphous solid dispersions (ASDs) have emerged as a well-established and commercially validated platform for enabling poorly soluble APIs. This strategy continues to garner significant attention for its potential to enhance the solubility and bioavailability of LUM, as demonstrated in recent in vitro and in vivo studies (Bhujbal et al., 2021b, Li et al., 2024, Takale et al., 2022). By maintaining the drug in a disordered, high-energy state, ASDs facilitate supersaturation upon dissolution, therefore improving absorption (Murdande et al., 2010). However, this supersaturated state is thermodynamically unstable and prone to recrystallisation both in solution and during storage. Consequently, polymers are incorporated in binary ASDs (BASDs) to stabilise the amorphous APIs and maintain supersaturation during dissolution. Polymer selection is thus a critical element in ASD development, requiring a balance between solid-state stability and dissolution enhancement (Yu et al., 2022, Zhao et al., 2022).

It has been reported that LUM BASDs formulated with a hydrophilic polymer, polyvinylpyrrolidone–vinyl acetate copolymer (PVPVA), exhibit superior dissolution performance compared with those based on enteric polymers, whose strong acid–base interactions with the drug can stabilise the amorphous form but compromise drug dissolution efficiency (Hiew et al., 2021). In addition to anionic enteric polymers, a cationic polymer (Eudragit® EPO) has also been investigated for LUM ASD formulation and was reported to enable more effective pH-shift dissolution of LUM than a neutral polymer, PVPVA, and an anionic polymer, HPMCAS, respectively. The authors attributed the superior performance of the LUM-EPO ASD to rapid EPO dissolution in the acid stage, which enabled an early onset of drug release (Frank et al., 2022). Other hydrophilic polymers, notably polyvinylpyrrolidone (PVP) and Soluplus®, have demonstrated considerable potential in enhancing solubility, in vitro drug release and in vivo pharmacokinetic performance of LUM ASD systems (Kanojiya et al., 2022, Li et al., 2024, Charde, 2021). The present study limits preliminary polymer screening to the neutral hydrophilic candidates PVP, PVPVA, and Soluplus®, without explicitly investigating polymer ionisation effects on LUM ASD performance.

Among the formulation variables affecting ASD performance, drug loading (DL) represents a central yet often underexplored parameter. Although increasing DL is desirable for high-dose drugs like LUM to minimise tablet size and reduce pill burden, it inevitably decreases the proportion of polymer responsible for drug stabilisation and solubilisation. Higher DLs are generally associated with reduced performance, whilst the extent of their detrimental impact can vary widely. In some cases, increasing DL may lead to negligible changes; in others, it may significantly impair either dissolution or physical stability (Fan et al., 2025, Keßler et al., 2025, Shetty et al., 2025, Zhang et al., 2021). Although efforts have been made to determine an upper limit of DL that ensures both sufficient dissolution and stability for specific drug-polymer (D-P) systems, the relationship between DL and ASD performance is far from well-studied. It is highly dependent on the physicochemical properties of individual API and its compatibility with different polymer carriers (Di et al., 2024, Shi et al., 2022, Xiang et al., 2025).

For LUM, presumably due to its severely low inherent solubility, the dissolution benefits conferred by BASDs remain insufficient. A feasible strategy for optimising BASD is the development of ternary ASDs (TASDs), wherein an additional component, such as a surfactant, is incorporated to further enhance dissolution and oral bioavailability (Li et al., 2023). However, the development of surfactant-containing TASDs for LUM is reported scarcely in the literature.

Surfactants are typically integrated to enhance wettability and promote solubilisation through micelle formation when present above their critical micelle concentrations (CMCs) (Jin et al., 2021). While numerous studies have demonstrated the remarkable efficacy of surfactants in further improving the dissolution of ASDs (Borde et al., 2021, Yang et al., 2023), others have reported that certain surfactants may interfere with polymer function by competitively interacting with polymer and destabilise drug supersaturation. Such effects have been observed both during the dissolution of fully fabricated ASDs (Chen et al., 2016, Deshpande et al., 2018, Pui et al., 2018) and in model drug–excipient solution studies (Wang et al., 2020, Zhang et al., 2019). These contradictory effects have attracted growing research interest to surfactant inclusion, which adds another layer of complexity to compositional ratios in ASD systems, especially under varying DLs. Moreover, several studies have suggested that surfactants may raise the limit of congruency, thus improving drug release at high DLs (Saboo et al., 2021, Yang et al., 2022).

To this end, the present study systematically investigates the influence of drug loading (10–50%) on the physical stability and drug release behaviour of binary and ternary ASDs of LUM, manufactured via hot-melt extrusion (HME), a widely adopted approach for ASD production. TASDs were formulated by incorporating a fixed surfactant fraction (10% w/w of the total formulation mass), replacing an equivalent fraction of the polymer. This design ensured a constant surfactant content across all TASDs, while the relative proportions of polymer and surfactant in the formulations decreased progressively with increasing DL. Such an approach enables a direct evaluation of how the inclusion of a certain amount of surfactant modifies TASD performance relative to BASDs across varying DLs. Both fresh and stored formulations were examined to capture DL-dependent effects on physical stability and drug release upon storage. In addition, micellisation during dissolution was explored as a key mechanistic factor, with particular attention to how DL influences the size and uniformity of self-assembled micelles and, consequently, the drug release performance in both binary and ternary systems. Overall, this work aims to elucidate the nuanced effects of DL variation in BASD and TASD systems, offering empirical evidence and mechanistic insights to support the rational design of ASDs for high-dose, poorly soluble drugs.