Stable amorphous solid dispersion of flubendazole with high loading via electrospinning.

In this work, an important step is taken towards the bioavailability improvement of poorly water-soluble drugs, such as flubendazole (Flu), posing a challenge in the current development of many novel oral-administrable therapeutics. Solvent electrospinning of a solution of the drug and poly (2-ethyl-2-oxazoline) (PEtOx) is demonstrated to be a viable strategy to produce stable nanofibrous amorphous solid dispersions (ASDs) with ultrahigh drug-loadings (up to 55 wt% Flu) and long-term stability (at least one year). Importantly, at such high drug loadings, the concentration of the polymer in the electrospinning solution has to be lowered below the concentration where it can be spun in absence of the drug as the interactions between the polymer and the drug result in increased solution viscosity. A combination of experimental analysis and molecular dynamics simulations revealed that this formulation strategy provides strong, dominant and highly stable hydrogen bonds between the polymer and the drug, which is crucial to obtain the high drug-loadings and to preserve the long-term amorphous character of the ASDs upon storage. In vitro drug release studies confirm the remarkable potential of this electrospinning formulation strategy by significantly increased drug solubility values and dissolution rates (respectively tripled and quadrupled compared to the crystalline drug), even after storing the formulation for one year.

Brønsted Acid Catalyzed Tandem Defunctionalization of Biorenewable Ferulic acid and Derivates into Bio-Catechol.

An efficient conversion of biorenewable ferulic acid into bio-catechol has been developed. The transformation comprises two consecutive defunctionalizations of the substrate, that is, C-O (demethylation) and C-C (de-2-carboxyvinylation) bond cleavage, occurring in one step. The process only requires heating of ferulic acid with HCl (or H2 SO4 ) as catalyst in pressurized hot water (250 °C, 50 bar N2 ). The versatility is shown on a variety of other (biorenewable) substrates yielding up to 84 % di- (catechol, resorcinol, hydroquinone) and trihydroxybenzenes (pyrogallol, hydroxyquinol), in most cases just requiring simple extraction as work-up.

A Switchable Domino Process for the Construction of Novel CO2 -Sourced Sulfur-Containing Building Blocks and Polymers.

α-Alkylidene cyclic carbonates (αCCs) recently emerged as attractive CO2 -sourced synthons for the construction of complex organic molecules. Herein, we report the transformation of αCCs into novel families of sulfur-containing compounds by organocatalyzed chemoselective addition of thiols, following a domino process that is switched on/off depending on the desired product. The process is extremely fast and versatile in substrate scope, provides selectively linear thiocarbonates or elusive tetrasubstituted ethylene carbonates with high yields following a 100 % atom economy reaction, and valorizes CO2 as a renewable feedstock. It is also exploited to produce a large diversity of unprecedented functional polymers. It constitutes a robust platform for the design of new sulfur-containing organic synthons and important families of polymers.

Reactivity of 3-Oxo-ß-lactams with Respect to Primary Amines-An Experimental and Computational Approach.

The reactivity of 3-oxo-ß-lactams with respect to primary amines was investigated in depth. Depending on the specific azetidin-2-one C4 substituent, this reaction was shown to selectively produce 3-imino-ß-lactams (through dehydration), α-aminoamides (through CO elimination), or ethanediamides (through an unprecedented C3-C4 ring opening). In addition to the experimental results, the mechanisms and factors governing these peculiar transformations were also examined and elucidated by means of DFT calculations.