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

Abstract

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) 1 H 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 hydrogenbonding 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.

Toward Developing Discriminating Dissolution Methods for Formulations Containing Nanoparticulates in Solution: The Impact of Particle Drift and Drug Activity in Solution

“…The micelle-associated E2 diffusion coefficient used in this study was determined at SR = 2, which served as a midpoint in concentration, where the maximum concentration is at the amorphous solubility or SR = 3.5. That value for the diffusion coefficient was selected as it has been observed that D mic decreases with increasing supersaturation as micelles incorporate more molecules of E2 within their structure …”

“…That value for the diffusion coefficient was selected as it has been observed that D mic decreases with increasing supersaturation as micelles incorporate more molecules of E2 within their structure. 77 Through the use of the effective permeability correction factor, it becomes possible to accurately understand the thermodynamic activity of an API in complex media. By correlating the corrected observed flux to the calibration curve developed, the unbound drug concentration was determined, and various thermodynamic parameters were calculated and are summarized in Table 3.…”

Unveiling the Role of Nonionic Surfactants in Enhancing Cefotaxime Drug Solubility: A UV-Visible Spectroscopic Investigation in Single and Mixed Micellar Formulations

“…Micellar systems employ a solubilization technique by encapsulating the Active Pharmaceutical Ingredient (API), i.e., the drug, within their hydrophobic cores, typically formed by surfactant molecules. This encapsulation process enables hydrophobic drugs, which have poor solubility in water, to be incorporated and dispersed in the aqueous environment of the micellar solution [26]. The hydrophobic tails of surfactant molecules surround the drug, shielding it from the aqueous medium.…”

Fast Dynamics of Difluprednate in Micelles or Swollen-Micelles Revealed by 19F Nuclear Magnetic Resonance Spin Relaxation Rates

“…Amphiphilic surfactant molecules assemble into nanometer (nm) sized micelle globules, which are dispersed in an aqueous solution. Micelles can be utilized to encapsulate hydrophobic drug molecules. − Additionally, oil can be incorporated into a micelle structure to enhance drug solubility, forming swollen micelles (s-micelles) or microemulsion (ME) globules (Figure A). , Viscosities of both surfactant and oil are 2 orders of magnitude higher than that of water; however, little is known about the dynamics of drug molecules in the viscous hydrophobic phase inside micelles. Knowledge of rotational motion is critical to explain NMR peak line shape and assess the applicability and accuracy of quantitative NMR (qNMR).…”