(W0930-09-59) A Systematic Study of the Plasticizing Effect of Phospholipids with Various Amounts of Hydrogenated Phosphatidylcholine

Purpose: The majority of the new chemical entities in the R&D pipeline are characterized by poor solubility and thus limited bioavailability [1]. One of the approaches to overcome the poor solubility is the use of amorphous solid dispersions (ASDs) as an enabling formulation. In this study, sorafenib (SOR), a kinase inhibitor drug belonging to BCS Class II, meaning it is poorly soluble, but well permeable, was selected as a model compound.  Phospholipids are amphiphilic molecules with favorable physicochemical properties, making them versatile as functional excipients, e.g., as solubilizers, wetting agents, emulsifiers, and structural components within drug delivery systems [2]. The purpose of this work was to identify the suitability of phospholipids for use in ASDs and their potential role as plasticizers.

Methods: The plasticizing effect of three phospholipid blends containing varying amounts of hydrogenated phosphatidylcholine (Phospholipon® P90H, >90% of hydrgenated phosphatidylcholine, P90H, Lipoid® P75-3 >70% of hydrogenated phosphatidylcholine P75-3, and egg yolk phosphatidylcholine E80, containing more than 80% of 1-palmitoyl-2-oleoylphosphatidylcholine POPC, E80), Kollidon® VA64) and hydroxypropyl methylcellulose acetate succinate (HPMCAS-MMP). The physical mixtures (PMs) at selected ratios presented in Table 1 were put in 2 mL reaction vials, with glass beads and mixed on a ball mill for 5 minutes at 15 Hz. DSC measurements were conducted using a DSC 214 Polyma (Netzsch, Germany). Approximately 5-10 mg of each sample was accurately weighed and sealed in pierced aluminum DSC pans. The samples were heated from 20 °C to 200 °C at a constant rate of 10 °C/min in 3 heating and cooling cycles. Samples were held at the endpoints for 2 minutes to ensure equilibration. Thermograms of the third heating runs were analyzed using the NETZSCH Proteus Thermal Analysis software.

Results: DSC analysis demonstrated a clear plasticizing effect of all tested phospholipids (E80, P75-3, and P90H) in sorafenib PMs, with variations depending on the polymer used. In HPMCAS-based systems, a consistent, phospholipid content-dependent reduction in polymer glass transition temperature (T_g) was observed. E80 exhibited a linear decrease in T_g, while P75-3 and P90H induced the most pronounced T_g reductions at 5% and 10% phospholipid content, respectively, suggesting a stronger plasticizing effect. In contrast, hydrogenated phospholipids showed a much milder plasticizing effect in VA64-based blends. T_g values for all phospholipid types decreased only slightly across the 0.5–10% concentration range, with less pronounced changes compared to HPMCAS. Notably, none of the VA64 formulations containing phospholipids exhibited a significant T_g reduction.

Conclusion: This study clearly demonstrated that phospholipids, particularly blends containing hydrogenated phospholipids such as P90H and P75-3, exhibit a plasticizing effect. The observed reduction in glass transition temperature (T_g) with increasing phospholipid concentration indicates enhanced polymer chain mobility, which can facilitate the hot-melt extrusion (HME) process. Among the tested phospholipids, the most pronounced T_g decrease was observed with 5% P75-3, while E80 exhibited the most consistent and linear T_g reduction, especially within the HPMCAS matrix. These findings support the role of phospholipids as effective plasticizers in advanced formulations manufactured using melting techniques. The use of phospholipids enables lower processing temperatures, improved homogeneity of extrudates or melts, and stabilization of the drug substance in the amorphous state.

References: Khan KU, Minhas MU, Badshah SF, Suhail M, Ahmad A, Ijaz S. Overview of nanoparticulate strategies for solubility enhancement of poorly soluble drugs. Life Sci. 2022;291:120301.
2. Fong SYK, Brandl M, Bauer-Brandl A. Phospholipid-based solid drug formulations for oral bioavailability enhancement: A meta-analysis. Eur J Pharm Sci. 2015;80:89–110.

Acknowledgements: The authors acknowledge financial support from the National Science Center Poland under grant No 2024/53/N/NZ7/02404