(M1130-01-06) Role of Temperature in the Formation of Solid Micellar-Size Nanoparticles of Nonionic Polyoxyethylated Amphiphiles

Purpose: In drug development and delivery, the limited aqueous solubility of many compounds poses a substantial obstacle. To address this challenge, micellar solubilization techniques are frequently utilized¹. Despite their widespread application, micellar systems are susceptible to dissociation and encounter stability issues upon dilution, which can compromise their effectiveness in solubilizing poorly water-soluble drugs. Solid micellar-size nanoparticles (SMNP) of the nonionic polyoxyethylated amphiphile such as, Brij^®76 demonstrate enhanced solubility, stability and anti-dilution properties², largely due to the temperature dependence of the physical state of nanoparticles in the formulation process and resulted formulation. Therefore, the purpose of this project is to further elucidate the influence of temperature on formation of nanoparticles of Brij^®76 for design and formulation processing of SMNP.

Methods: Solid micellar-size nanoparticles (SMNP) consisting of only Brij^®76 POE (10) stearyl ether were prepared with either centrimonium chloride (CTAC) or sodium lauryl sulfate (SLS) by forming a solution above 45 °C and quenching at 0 °C. The equilibrium solubility of Brij®76 was examined using the shake-flask method. Phase changes respective to temperature were observed after shaking in a water bath over 24 hours. Particle size analysis was conducted using the Zetasizer 3000HS (Malvern Instruments Ltd, UK), while images were acquired using the Glacios 200kV CryoTEM (ThermoFisher, USA). Thermal analysis of quenched SMNPs was performed using a NanoDSC (TA Instruments, USA).

Results: Brij^®76 at temperatures 25 °C, 37.5 °C, 42 °C, and 45 °C were 36.11 mg/mL, 65.23 mg/mL, 110.78 mg/mL, and 120.03 mg/mL, respectively (Figure 1). At 50°C, Brij^®76 was freely soluble in a fixed volume of distilled water, forming increasingly viscous solutions with increasing amounts of solid surfactant. The solubility observed at and above 50 °C was greater than 500 mg/mL. For all weight percentages of Brij^®76 across the same temperature intervals, there is a discernible shift from a binary phase system, characterized by solid and liquid phases, to a single-phase state, occurring at a temperature of 45 °C (Figure 2). This is further corroborated by DSC data, where the T_max during the phase change from solid to liquid is 44.97 °C (Figure 3). There were no two phases observed above this temperature when mixing with water. Particle sizes of quenched samples Brij^®76, along with 0.5%, 1%, 5%, and 10% SLS and CTAC formulations, were 52.23 ± 8.45 nm, 50.6 ± 5.5 nm, 29.23 ± 2.6 nm, 34.22 ± 3.4 nm, 55.41 ± 5.3 nm, and 42.16 ± 1.1 nm, 39.79 ± 2.1 nm, 47.91 ± 3.1 nm, and 48.61 ± 2.9 nm, respectively (Table 1). CryoTEM imaging confirms the size and morphology of the SMNP, with quenched samples exhibiting spherical nanoparticles around 30 nm (Figure 4A). Non-quenched samples show significantly larger particle sizes and ellipsoidal morphology (Figure 4B), along with visible aggregation (Figure 4C).

Conclusion: This study showed the importance of temperature as a critical factor in the formation, shape and properties of SMNP formulations. Based on the solubility profile of Brij^®76 and its phase transitions across various temperatures, the temperature of 45 °C is a pivotal temperature threshold for the formulation of Brij^®76 SMNP. By dissolving solid surfactant above this threshold and rapidly quenching the solution, a two-phase system can be created and maintained at normal body temperature of 37.5 °C. This provides the basis for designing a micellar-like nanoparticle system demonstrating the anti-dilution properties and enhanced stability against dissociation.

References: Gao, Xiaoling et al. “Design and preparation of nanostructures based on Krafft point of nonionic amphiphiles for delivery of poorly water-soluble compounds.” International journal of pharmaceutics vol. 588 (2020): 119789. doi:10.1016/j.ijpharm.2020.119789

Li, J. (2024, July 8–12). Thermodynamic Insights into the Enhanced Stability and Anti-dilution Properties of Solid Micellar-size Nanoparticles [Accepted conference presentation abstract]. Controlled Release Society 2024 Annual Meeting and Exposition, Bologna, Italy.




Figure 4: CryoTEM imaging of quenched and non-quenched solid micellar-size nanoparticles at 45,000x magnification.
A) Quenched 1% SLS
B) Non-quenched 1% SLS
C) Non-quenched Brij®76 only