STUDIES ON DRUG SOLUBILIZATION MECHANISM IN SIMPLE MICELLE SYSTEMS

Poor aqueous solubilities of drug candidates limit the biopharmaceutical usefulness in either oral or parenteral dosage forms. Lipid assemblies, such as micelles, may provide a means of enhancing solubility. Despite their usefulness, little is known about the means by which micelles accomplish this result. The goal of the current dissertation is to provide the molecular level understanding of the mechanism by which simple micelle systems solubilize drugs. Specifically, the location, orientation and amount of the drug molecules in micelle systems are the focuses of the work. Three series of model drugs, steroids, benzodiazepines and parabens, in three surfactant systems with anionic, cationic and neutral hydrophilic headgroups were studied. Solubilization power of each micelle system for each model drug was determined by equilibrium solubility. The observed strong surface activities of model drug at hydrocarbon/water interface and the ability of the drugs to compete with surfactants for the model oil/water interface lend support to the hypothesis that drug molecules are mainly solubilized in the interfacial region of the micelles. A surface-localized thermodynamic model that considered the surfactant-drug competition at micelle surface was successfully applied to predict the micelle/water partitioning coefficients. The predictions were made without the use of adjustable parameters in the case of both dilute and concentrated solutions. The orientation of drug at micelle surface was determined by matching calculated occupied areas by solutes at oil/water interface using molecular modeling method to the experimental values. To look into the micro-structure of micelles, twodimensional and diffusion (or PGSE) NMR techniques were employed to detect the specific drug-surfactant interactions and the micelle sizes influenced by model drugs and electrolytes

Tunable Correlated Chern Insulator and Ferromagnetism in Trilayer Graphene/Boron Nitride Moir\'e Superlattice

Studies on two-dimensional electron systems in a strong magnetic field first revealed the quantum Hall (QH) effect, a topological state of matter featuring a finite Chern number (C) and chiral edge states. Haldane later theorized that Chern insulators with integer QH effects could appear in lattice models with complex hopping parameters even at zero magnetic field. The ABC-trilayer graphene/hexagonal boron nitride (TLG/hBN) moir\'e superlattice provides an attractive platform to explore Chern insulators because it features nearly flat moir\'e minibands with a valley-dependent electrically tunable Chern number. Here we report the experimental observation of a correlated Chern insulator in a TLG/hBN moir\'e superlattice. We show that reversing the direction of the applied vertical electric field switches TLG/hBN's moir\'e minibands between zero and finite Chern numbers, as revealed by dramatic changes in magneto-transport behavior. For topological hole minibands tuned to have a finite Chern number, we focus on 1/4 filling, corresponding to one hole per moir\'e unit cell. The Hall resistance is well quantized at h/2e2, i.e. C = 2, for |B| > 0.4 T. The correlated Chern insulator is ferromagnetic, exhibiting significant magnetic hysteresis and a large anomalous Hall signal at zero magnetic field. Our discovery of a C = 2 Chern insulator at zero magnetic field should open up exciting opportunities for discovering novel correlated topological states, possibly with novel topological excitations, in nearly flat and topologically nontrivial moir\'e minibands.Comment: 16 pages, 4 figures, and 2 extended figure

Effects of impurity scattering on electron-phonon resonances in semiconductor superlattice high-field transport

A non-equilibrium Green's function method is applied to model high-field quantum transport and electron-phonon resonances in semiconductor superlattices. The field-dependent density of states for elastic (impurity) scattering is found non-perturbatively in an approach which can be applied to both high and low electric fields. I-V curves, and specifically electron-phonon resonances, are calculated by treating the inelastic (LO phonon) scattering perturbatively. Calculations show how strong impurity scattering suppresses the electron-phonon resonance peaks in I-V curves, and their detailed sensitivity to the size, strength and concentration of impurities.Comment: 7 figures, 1 tabl

Competition of Hydrophobic Steroids with Sodium Dodecyl Sulfate, Dodecyltrimethylammonium Bromide, or Dodecyl β‑d‑maltoside for the Dodecane/Water Interface

The surface tension lowering abilities of insoluble steroids, progesterone and testosterone, were examined at the dodecane/water interface in the presence and absence of surfactants, sodium dodecyl sulfate, dodecyltrimethylammonium bromide, and dodecyl maltoside. In the absence of these surfactants, the steroids significantly lowered the interfacial tension while exhibiting no activity at the air/water and air/dodecane surfaces. Further, in mixtures of surfactants and steroids, significant enhancement of interfacial tension lowering was observed. At a sufficiently high concentration of surfactant, no further lowering of tension was observed in the presence of the steroids. The synergistic effects on interfacial tension of steroids and surfactants were characterized by the free energy of transfer to the interface of each solute based on a two-dimensional solution equation of state. Assuming no significant interaction between the steroids and the surfactants in the interface, predictions of interfacial tensions were made based on the calculated free energies of transfer and interfacial area occupied. Good agreement was found between the predicted values and experimental values for interfacial tension. The results of these studies show that progesterone and testosterone, molecules not normally thought of as surface active, exhibit significant interfacial activity and can successfully compete with surfactants for the dodecane/water interface

Non-isothermal stability by linear heating: a fast method for preformulation stability screening of drugs at the discovery and development interface

Abstract The non-isothermal method for prediction of chemical stability of pharmaceuticals has been discussed in the literature for almost half a century but it has not yet been systematically evaluated. The purpose of this study was to carry out a comprehensive experimental evaluation of the non-isothermal method against the conventional isothermal method for a fast preformulation stability screening. The chemical stabilities of 20 pharmaceutical compounds in aqueous based solution were investigated. Degradation rate constants (k), activation energies (E a), t 90% and t 98% (times for 10 and 2% loss of potency, respectively) were determined by applying the Arrhenius equation to stability data generated by both non-isothermal and isothermal methods. A comparison of the results indicated that the ‘1 week’ non-isothermal experiment is as accurate as the ‘8 weeks’ isothermal experiment for placing compounds (15 out of 16 cases) into the same binning categories based on t 90% and t98% values. The absolute values of k, t 90% and t98% at 25 °C determined by the non-isothermal method for compounds with first order (or pseudo-first order) degradation kinetics were within a factor of two compared to those determined by the isothermal method. The non-isothermal method proved to be not applicable for accurate prediction of the shelf-lives of pharmaceuticals, however, when used to bin discovery compounds based on likely issues related to chemical instability, the non-isothermal method can be carefully implemented as a cost effective, fast, and relatively ‘high-throughput’ method to support drug stability screening at the discovery and development interface