Mechanistic Investigation of Drug Supersaturation in the Presence of Polysorbates as Solubilizing Additives by Solution Nuclear Magnetic Resonance Spectroscopy

• Published in: Molecular pharmaceutics Vol. 18; no. 12; pp. 4310 - 4321
• Main Authors: Lu, Xingyu, Li, Mingyue, Arce, Freddy A, Ling, Jing, Setiawan, Nico, Wang, Yaqiang, Shi, Xiaohuo, Campbell, Heather R, Nethercott, Matthew J, Xu, Wei, Munson, Eric J, Marsac, Patrick J, Su, Yongchao
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 06-12-2021
• Subjects: Crystallization; Estradiol - chemistry; Magnetic Resonance Spectroscopy - methods; Micelles; Molecular Docking Simulation; Particle Size; Polysorbates - chemistry; Solubility; lipid formulation; micelle; NMR; polysorbate; drug interaction; 17β-Estradiol; supersaturation; surfactant
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.1c00477

The introduction of solubilizing additives has historically been an attractive approach to address the ever-growing proportion of poorly water-soluble drug (PWSD) compounds within the modern drug discovery pipeline. Lipid-formulations, and more specifically micelle formulations, have garnered particular interest because of their simplicity, size, scalability, and avoidance of solid-state limitations. Although micelle formulations have been widely utilized, the molecular mechanism of drug solubilization in surfactant micelles is still poorly understood. In this study, a series of modern nuclear magnetic resonance (NMR) methods are utilized to gain a molecular-level understanding of intermolecular interactions and kinetics in a model system. This approach enabled the understanding of how a PWSD, 17β-Estradiol (E2), solubilizes within a nonionic micelle system composed of polysorbate 80 (PS80). Based on one-dimensional (1D) 1H chemical shift differences of E2 in PS80 solutions, as well as intermolecular correlations established from 1D selective nuclear Overhauser effect (NOE) and two-dimensional NOE spectroscopy experiments, E2 was found to accumulate within the palisade layer of PS80 micelles. A potential hydrogen-bonding interaction between a hydroxyl group of E2 and a carbonyl group of PS80 alkane chains may allow for stabilizing E2–PS80 mixed micelles. Diffusion and relaxation NMR analysis and particle size measurements using dynamic light scattering indicate a slight increase in the micellar size with increasing degrees of supersaturation, resulting in slower mobility of the drug molecule. Based on these structural findings, a theoretical orientation model of E2 molecules with PS80 molecules was developed and validated by computational docking simulations.