Efficient Synthesis of Submicrometer-Sized Active Pharmaceuticals by Laser Fragmentation in a Liquid-Jet Passage Reactor with Minimum Degradation

One challenge in the development of new drug formulations is overcoming their low solubility in relevant aqueous media. Reducing the particle size of drug powders to a few hundred nanometers is a well-known method that leads to an increase in solubility due to an elevated total surface area. However, state-of-the-art comminution techniques like cryo-milling suffer from degradation and contamination of the drugs, particularly when sub-micrometer diameters are aspired that require long processing times. In this work, picosecond-pulsed laser fragmentation in liquids (LFL) of dispersed drug particles in a liquid-jet passage reactor is used as a wear-free comminution technique using the hydrophobic oral model drugs naproxen, prednisolone, ketoconazole, and megestrol acetate. Particle size and morphology of the drug particles are characterized using scanning electron microscopy (SEM) and changes in particle size distributions upon irradiation are quantified using an analytical centrifuge. The findings highlight the superior fragmentation efficiency of the liquid-jet passage reactor setup, with a 100 times higher fraction of submicrometer particles (SMP) of the drugs compared to the batch control, which enhances solubility and goes along with minimal chemical degradation (<1%), determined by attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR), high-performance liquid chromatography (HPLC), and X-ray diffraction (XRD). Moreover, the underlying predominantly photo-mechanically induced laser fragmentation mechanisms of organic microparticles (MP) are discussed.     

Synthesis of 5-acetyloxazoles and 1,2-diketones from β-alkoxy-β-ketoenamides and their subsequent transformations

Lithiated alkoxyallenes, nitriles, and carboxylic acids have been employed as precursors in a three-component reaction leading to highly substituted β-alkoxy-β-ketoenamides. Upon treatment with trifluoroacetic acid, these enamides could be easily cyclized to 5-acetyloxazole derivatives. The synthesis is very flexible with respect to the substitution pattern at C-2 and C-4 of the oxazole core. A mechanistic suggestion for the oxazole formation is presented on the basis of (18)O-labeled compounds and their mass spectrometric analysis. In several cases, 1,2-diketones are formed as side products or even as major components. The acetyl moiety at C-5 of the oxazole derivatives can efficiently be converted into alkenyl or alkynyl moieties, which allows a multitude of subsequent reactions. Condensation reactions of the acetyl group provided the expected oxime or hydrazone. By applying a Fischer reaction, the phenylhydrazone could be transferred into an indole, which emphasizes the potential of 5-acetyloxazoles for the preparation of highly substituted (poly)heterocyclic systems. The alkynyl group at C-2 is prone to addition reactions, providing an enamine with interesting photophysical properties. Sonogashira couplings were performed with 5-alkynyl-substituted oxazoles, furnishing the expected aryl-substituted products. This alkynyl unit was employed for the preparation of a new, star-shaped trisoxazole derivative. The ability of this multivalent compound to form self-assembled monolayers between the basal plane of highly oriented pyrolytic graphite and 1-phenyloctane was demonstrated by scanning tunneling microscopy (STM). The star-shaped compound seems to prefer the C(3)-symmetric arrangement in this two-dimensional crystal. Two 1,2-diketones were smoothly converted into functionalized quinoxaline derivatives.     

Early development drug formulation on a chip: fabrication of nanoparticles using a microfluidic spray dryer

Early development drug formulation is exacerbated by increasingly poor bioavailability of potential candidates. Prevention of attrition due to formulation problems necessitates physicochemical analysis and formulation studies at a very early stage during development, where the availability of a new substance is limited to small quantities, thus impeding extensive experiments. Miniaturization of common formulation processes is a strategy to overcome those limitations. We present a versatile technique for fabricating drug nanoformulations using a microfluidic spray dryer. Nanoparticles are formed by evaporative precipitation of the drug-loaded spray in air at room temperature. Using danazol as a model drug, amorphous nanoparticles of 20-60 nm in diameter are prepared with a narrow size distribution. We design the device with a geometry that allows the injection of two separate solvent streams, thus enabling co-spray drying of two substances for the production of drug co-precipitates with tailor-made composition for optimization of therapeutic efficiency.     

Selective covalent conjugation of phosphorothioate DNA oligonucleotides with streptavidin

Protein-DNA conjugates have found numerous applications in the field of diagnostics and nanobiotechnology, however, their intrinsic susceptibility to DNA degradation by nucleases represents a major obstacle for many applications. We here report the selective covalent conjugation of the protein streptavidin (STV) with phosphorothioate oligonucleotides (psDNA) containing a terminal alkylthiolgroup as the chemically addressable linking unit, using a heterobifunctional NHS-/maleimide crosslinker. The psDNA-STV conjugates were synthesized in about 10% isolated yields. We demonstrate that the terminal alkylthiol group selectively reacts with the maleimide while the backbone sulfur atoms are not engaged in chemical conjugation. The novel psDNA-STV conjugates retain their binding capabilities for both biotinylated macromolecules and the complementary nucleic acid. Moreover, the psDNA-STV conjugate retained its binding capacity for complementary oligomers even after a nuclease digestion step, which effectively degrades deoxyribonucleotide oligomers and thus the binding capability of regular DNA-STV conjugates. The psDNA-STV therefore hold particular promise for applications e.g. in proteome research and novel biosensing devices, where interfering endogenous nucleic acids need to be removed from analytes by nuclease digestion.     

The Shapley value of exact assignment games

We prove that the Shapley value of every two-sided exact assignment game lies in the core of the game.