In situ setup for screening of drug permeation by NMR spectroscopy.

There are various commercially available setups for studying drug permeation, which differ in cost and manual labor. We explore an artificial membrane in an NMR tube to assess drug permeation with automated measurements. NMR-based concentrations were validated with HPLC and compared to a conventional setup. Setup-specific challenges and workarounds as well as future setup-designs for this and other applications are discussed.

Bile Is a Selective Elevator for Mucosal Mechanics and Transport.

Mucus mechanically protects the intestinal epithelium and impacts the absorption of drugs, with a largely unknown role for bile. We explored the impacts of bile on mucosal biomechanics and drug transport within mucus. Bile diffused with square-root-of-time kinetics and interplayed with mucus, leading to transient stiffening captured in Brillouin images and a concentration-dependent change from subdiffusive to Brownian-like diffusion kinetics within the mucus demonstrated by differential dynamic microscopy. Bile-interacting drugs, Fluphenazine and Perphenazine, diffused faster through mucus in the presence of bile, while Metoprolol, a drug with no bile interaction, displayed consistent diffusion. Our findings were corroborated by rat studies, where co-dosing of a bile acid sequestrant substantially reduced the bioavailability of Perphenazine but not Metoprolol. We clustered over 50 drugs based on their interactions with bile and mucin. Drugs that interacted with bile also interacted with mucin but not vice versa. This study detailed the dynamics of mucus biomechanics under bile exposure and linked the ability of a drug to interact with bile to its abbility to interact with mucus.

Structural Investigation on How Guest Loading of Poly(2-oxazoline)-Based Micelles Affects the Interaction with Simulated Intestinal Fluids.

Drug loading of polymer micelles can have a profound effect on their particle size and morphology as well as their physicochemical properties. In turn, this influences performance in biological environments. For oral delivery of drugs, the intestinal environment is key, and consequently, a thorough structural understanding of what happens at this material-biology interface is required to understand in vivo performance and tailor improved delivery vehicles. In this study, we address this interface in vitro through a detailed structural characterization of the colloidal assemblies of polymeric micelles based on poly(2-oxazolines) with three different guest loadings with the natural product curcumin (17-52 wt %) in fed-state simulated intestinal fluids (FeSSIF). For this, we employ NMR spectroscopy, in particular, 1H NMR, 1H-1H-NOESY, and 1H DOSY experiments complemented by quantum chemical calculations and cryo-TEM measurements. Through this mixture of methods, we identified curcumin-taurocholate interactions as central interaction patterns alongside interactions with the polymer and lipids. Furthermore, curcumin molecules can be exchanged between polymer micelles and bile colloids, an important prerequisite for their uptake. Finally, increased loading of the polymer micelles with curcumin resulted in a larger number of vesicles as taurocholate─through coordination with Cur─is less available to form nanoparticles with the lipids. The loading-dependent behavior found in this study deviates from previous work on a different drug substance highlighting the need for further studies including different drug molecules and polymer types to improve the understanding of events on the molecular level.

Harnessing Bile for Drug Absorption through Rational Excipient Selection.

Bile solubilization and apparent solubility at resorption sites critically affect the bioavailability of orally administered and poorly water-soluble drugs. Therefore, identification of drug-bile interaction may critically determine the overall formulation success. For the case of the drug candidate naporafenib, drug in solution at phase separation onset significantly improved with polyethylene glycol-40 hydrogenated castor oil (RH40) and amino methacrylate copolymer (Eudragit E) but not with hydroxypropyl cellulose (HPC) in both phosphate-buffered saline (PBS) and PBS supplemented with bile components. Naporafenib interacted with bile as determined by 1H and 2D 1H-1H nuclear magnetic resonance spectroscopy and so did Eudragit E and RH40 but not HPC. Flux across artificial membranes was reduced in the presence of Eudragit E. RH40 reduced the naporafenib supersaturation duration. HPC on the other side stabilized naporafenib's supersaturation and did not substantially impact flux. These insights on bile interaction correlated with pharmacokinetics (PK) in beagle dogs. HPC preserved naporafenib bile solubilization in contrast to Eudragit E and RH40, resulting in favorable PK.

Cyano(fluoro)borate and cyano(hydrido)borate ionic liquids: low-viscosity ionic media for electrochemical applications.

The synthesis and detailed characterization of low-viscosity room-temperature ionic liquids (RTILs) and [BnPh3P]+ salts with the cyano(fluoro)borate anions [BF(CN)3]- (MFB), [BF2(CN)2]- (DFB), and [BF3(CN)]- as well as the new mixed-substituted anion [BFH(CN)2]- (FHB) is described. The RTILs with [EMIm]+ or [BMPL]+ as countercations were obtained in yields of up to 98% from readily available alkali metal salts and in high purities that allow application in electrochemical devices. Trends in thermal stability, melting and freezing behavior, density, electrochemical stability, dynamic viscosity, specific conductivity and ion diffusivity have been assessed and compared to those of the related tetracyanoborate- and cyano(hydrido)borate-RTILs. The crystal structure analysis of the [BnPh3P]+ salts of [BFn(CN)4-n]- (n = 0-4), [BHn(CN)4-n]- (n = 1-3) and [BFH(CN)2]- provided experimental access to anion volumina that together with ion molecular mass, electrostatic potential, shape and chemical stability have been correlated to physicochemical properties. In addition, the cytotoxicity of the [EMIm]+-ILs and potassium or sodium salts was studied.

Synthesis and Fluorescence Studies of Diborene Coinage Metal Complexes.

Nine different coinage metal (Cu, Ag) π complexes of diborenes with various anionic diborene (aryl, heteroaryl) and metal substituents (Cl, Br, C6F5, C2SiMe3), stabilizing neutral donors (N-heterocyclic carbene = NHC, phosphine), configurations (cis/trans, acyclic/cyclic diborene), and charges (neutral, cationic) were synthesized and characterized by multinuclear NMR spectroscopy and X-ray crystallographic analyses. Their optical properties were investigated by UV-vis absorption and steady-state as well as time-resolved luminescence spectroscopy in solution and the solid state to gain insights into the excited-state behavior of this unusual class of photoactive compounds and to provide structure-property relationships. The structural and electronic modification of the (B═B)···M motif greatly influences not only the visible light absorption but also the photostability and quantum yields, which can reach high values of up to f = 0.42. The lifetimes are found in the nanosecond regime, providing estimated radiative rate constants over a wide range of kr = 1.3-14 × 107 s-1, indicative of fluorescence. Intersystem crossing (ISC) is sufficiently slow for prompt emission from the S1 state to be observed, while the spin-orbit coupling in the T1 state is too weak for phosphorescence to occur at room temperature. ISC can be accelerated, however, by modifying diborene ligand substitution and the coinage metal center, hinting at the potential for exploiting the properties of long-lived triplet excited states of metal diborene complexes in the future.

Concentration and composition dependent aggregation of Pluronic- and Poly-(2-oxazolin)-Efavirenz formulations in biorelevant media.

Many drugs and drug candidates are poorly water-soluble. Intestinal fluids play an important role in their solubilization. However, the interactions of intestinal fluids with polymer excipients, drugs and their formulations are not fully understood. Here, diffusion ordered spectroscopy (DOSY) and nuclear Overhauser effect spectroscopy (NOESY), complemented by cryo-TEM were employed to address this. Efavirenz (EFV) as model drug, the triblock copolymers Pluronic® F-127 (PF127) and poly(2-oxazoline) based pMeOx-b-pPrOzi-b-pMeOx (pOx/pOzi) and their respective formulations were studied in simulated fed-state intestinal fluid (FeSSIF). For the individual polymers, the bile interfering nature of PF127 was confirmed and pure pOx/pOzi was newly classified as non-interfering. A different and more complex behaviour was however observed if EFV was involved. PF127/EFV formulations in FeSSIF showed concentration dependent aggregation with separate colloids at low formulation concentrations, a merging of individual particles at the solubility limit of EFV in FeSSIF and joint aggregates above this concentration. In the case of pOx/pOzi/EFV formulations, coincident diffusion coefficients for pOx/pOzi, lipids and EFV indicate joint aggregates across the studied concentration range. This demonstrates that separate evaluation of polymers and drugs in biorelevant media is not sufficient and their mixtures need to be studied to learn about concentration and composition dependent behaviour.

Drug-Induced Dynamics of Bile Colloids.

Bile colloids containing taurocholate and lecithin are essential for the solubilization of hydrophobic molecules including poorly water-soluble drugs such as Perphenazine. We detail the impact of Perphenazine concentrations on taurocholate/lecithin colloids using analytical ultracentrifugation, dynamic light scattering, small-angle neutron scattering, nuclear magnetic resonance spectroscopy, coarse-grained molecular dynamics simulations, and isothermal titration calorimetry. Perphenazine impacted colloidal molecular arrangement, structure, and binding thermodynamics in a concentration-dependent manner. At low concentration, Perphenazine was integrated into stable and large taurocholate/lecithin colloids and close to lecithin. Integration of Perphenazine into these colloids was exothermic. At higher Perphenazine concentration, the taurocholate/lecithin colloids had an approximately 5-fold reduction in apparent hydrodynamic size, heat release was less exothermic upon drug integration into the colloids, and Perphenazine interacted with both lecithin and taurocholate. In addition, Perphenazine induced a morphological transition from vesicles to wormlike micelles as indicated by neutron scattering. Despite these surprising colloidal dynamics, these natural colloids successfully ensured stable relative amounts of free Perphenazine throughout the entire drug concentration range tested here. Future studies are required to further detail these findings both on a molecular structural basis and in terms of in vivo relevance.

Think Beyond the Core: Impact of the Hydrophilic Corona on Drug Solubilization Using Polymer Micelles.

Polymeric micelles are typically characterized as core-shell structures. The hydrophobic core is considered as a depot for hydrophobic molecules, and the corona-forming block acts as a stabilizing and solubilizing interface between the core and aqueous milieu. Tremendous efforts have been made to tune the hydrophobic block to increase the drug loading and stability of micelles, whereas the role of hydrophilic blocks is rarely investigated in this context, with poly(ethylene glycol) (PEG) being the gold standard of hydrophilic polymers. To better understand the role of the hydrophilic corona, a small library of structurally similar A-B-A-type amphiphiles based on poly(2-oxazoline)s and poly(2-oxazine)s is investigated by varying the hydrophilic block A utilizing poly(2-methyl-2-oxazoline) (pMeOx; A) or poly(2-ethyl-2-oxazoline) (pEtOx; A*). In terms of hydrophilicity, both polymers closely resemble PEG. The more hydrophobic block B bears either a poly(2-oxazoline) and poly(2-oxazine) backbone with C3 (propyl) and C4 (butyl) side chains. Surprisingly, major differences in loading capacities from A-B-A > A*-B-A > A*-B-A* is observed for the formulation with two poorly water-soluble compounds, curcumin and paclitaxel, highlighting the importance of the hydrophilic corona of polymer micelles used for drug formulation. The formulations are also characterized by various nuclear magnetic resonance spectroscopy methods, dynamic light scattering, cryogenic transmission electron microscopy, and (micro) differential scanning calorimetry. Our findings suggest that the interaction between the hydrophilic block and the guest molecule should be considered an important, but previously largely ignored, factor for the rational design of polymeric micelles.

Synthesis of cyclic diborenes with unprecedented cis-configuration.

The first examples of cis-configured diborenes - and the first cyclic diborenes - are isolated by taking advantage of stabilisation by chelating diphosphine ligands. The diborenes are prepared by a convenient one-pot reductive procedure that circumvents the need for a pre-formed base-adduct of the boron-containing precursor.