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.     

Design, synthesis and biological characterization of novel inhibitors of CD38

Human CD38 is a novel multi-functional protein that acts not only as an antigen for B-lymphocyte activation, but also as an enzyme catalyzing the synthesis of a Ca(2+) messenger molecule, cyclic ADP-ribose, from NAD(+). It is well established that this novel Ca(2+) signaling enzyme is responsible for regulating a wide range of physiological functions. Based on the crystal structure of the CD38/NAD(+) complex, we synthesized a series of simplified N-substituted nicotinamide derivatives (Compound 1-14). A number of these compounds exhibited moderate inhibition of the NAD(+) utilizing activity of CD38, with Compound 4 showing the highest potency. The crystal structure of CD38/Compound 4 complex and computer simulation of Compound 7 docking to CD38 show a significant role of the nicotinamide moiety and the distal aromatic group of the compounds for substrate recognition by the active site of CD38. Biologically, we showed that both Compounds 4 and 7 effectively relaxed the agonist-induced contraction of muscle preparations from rats and guinea pigs. This study is a rational design of inhibitors for CD38 that exhibit important physiological effects, and can serve as a model for future drug development.     

The importance of the N-H bond in Ru/TsDPEN complexes for asymmetric transfer hydrogenation of ketones and imines

Ru(II) complexes of TsDPEN containing two alkyl groups on the non-tosylated nitrogen atom are poor catalysts for asymmetric transfer hydrogenation of ketones and imines; this observation provides direct evidence for the importance of the N-H interaction in the transition state for ketone reduction.     

A generalized penalty function in Sparre Andersen risk models with surplus-dependent premium

In a general Sparre Andersen risk model with surplus-dependent premium income, the generalization of Gerber-Shiu function proposed by Cheung et al. (2010a) is studied. A general expression for such Gerber-Shiu function is derived, and it is shown that its determination reduces to the evaluation of a transition function which is independent of the penalty function. Properties of and explicit expressions for such a transition function are derived when the surplus process is subject to (i) constant premium; (ii) a threshold dividend strategy; or (iii) credit interest. Extension of the approach is discussed for an absolute ruin model with debit interest.     

Copper-mediated reduction of CO2 with pinB-SiMe2Ph via CO2 insertion into a copper-silicon bond

Reaction of [(IPr)Cu-OtBu] (1) with pinB-SiMe(2)Ph (2) leads to the Cu-silyl complex [(IPr)Cu-SiMe(2)Ph] (3). Insertion of CO(2) into the Cu-Si bond of 3 is followed by transformation of the resulting silanecarboxy complex [(IPr)Cu-O(2)CSiMe(2)Ph] (4) to the silanolate complex [(IPr)Cu-OSiMe(2)Ph] (5) via extrusion of CO. As 5 reacts readily with 2 to regenerate 3, a catalytic CO(2) reduction to CO is feasible. The individual steps were studied by in situ(13)C NMR spectroscopy of a series of stoichiometric reactions. Complexes 3, 4, and 5 were isolated and fully characterized, including single-crystal X-ray diffraction studies. Interestingly, the catalytic reduction of CO(2) using silylborane 2 as a stoichiometric reducing agent leads not only to CO and pinB-O-SiMe(2)Ph but also to PhMe(2)Si-CO(2)-SiMe(2)Ph as an additional reduction product.     

Cell receptor and surface ligand density effects on dynamic states of adhering circulating tumor cells

Dynamic states of cancer cells moving under shear flow in an antibody-functionalized microchannel are investigated experimentally and theoretically. The cell motion is analyzed with the aid of a simplified physical model featuring a receptor-coated rigid sphere moving above a solid surface with immobilized ligands. The motion of the sphere is described by the Langevin equation accounting for the hydrodynamic loadings, gravitational force, receptor-ligand bindings, and thermal fluctuations; the receptor-ligand bonds are modeled as linear springs. Depending on the applied shear flow rate, three dynamic states of cell motion have been identified: (i) free motion, (ii) rolling adhesion, and (iii) firm adhesion. Of particular interest is the fraction of captured circulating tumor cells, defined as the capture ratio, via specific receptor-ligand bonds. The cell capture ratio decreases with increasing shear flow rate with a characteristic rate. Based on both experimental and theoretical results, the characteristic flow rate increases monotonically with increasing either cell-receptor or surface-ligand density within certain ranges. Utilizing it as a scaling parameter, flow-rate dependent capture ratios for various cell-surface combinations collapse onto a single curve described by an exponential formula.     

Comparative Large Eddy Simulation study of a large-scale buoyant fire

A fully-coupled Large Eddy Simulation model which incorporates all essential combustion, radiation and soot chemistry considerations have been developed to simulate the temporal vortical structure of a large-scale buoyant fire. Numerical results are validated and compared against a full-scale fire measurements and predictions from other LES models. Quantitative comparisons against experimental data suggested that the present model successfully captured the vortical structures and the puffing behaviour of a buoyant fire.     

The properties of liquid nitrogen

The light-scattering ‘anisotropy’ spectrum of liquid nitrogen has been measured for the liquid along the liquid-vapour coexistence line from 69·4 K (almost the triple point) to near the critical point at 125 K and for the gas under pressure at 128 K. The spectrum is very broad (HWHH～50 cm^-1) due to rapid molecular reorientation. The molecular anisotropy spectrum is approximately gaussian, corresponding to a correlation time for molecular reorientation of order 2 × 10^-13 s at 80 K which is comparable with that obtained from nuclear magnetic resonance. A gaussian rather than a lorentzian form arises because molecular reorientation is not a ‘slow’ variable.

Above the critical temperature the molecular anisotropy spectrum can be roughly described as a collision-broadened rotational line spectrum.

The spectrum and its time Fourier Transform are analysed in terms of the dynamical correlation of orientation of the molecules.

A component of the spectrum due to induced polarization is separated from the anisotropy contribution by a study of the far wing of the spectrum and is observed on the Stokes side out to about 250 cm^-1. This depends exponentially on frequency shift and is interpreted in terms of molecular collision dynamics. The correlation time for this motion is about a factor three shorter than that for molecular reorientation.

The spectra are markedly asymmetric after all experimental corrections for asymmetry have been made. The asymmetry is shown to correspond to the detailed balance factor. It is pointed out that this factor should be allowed for in the case of induced scattering, in particular.

A theoretical analysis is given of the effect of correlation of molecular orientation on the light-scattering spectrum for centrosymmetric linear molecules. In particular it is shown that the normalized second moment of the spectrum is unaffected by correlation of orientation.     

The properties of liquid nitrogen

A Molecular Dynamics simulation of liquid nitrogen has been carried out using an atom-atom potential together with a point quadrupole-quadrupole interaction. The changes in the properties of the model fluid compared to a previous simulation [1] using the atom-atom potential alone are small but significant. The structure factor is notably closer to experiment. The properties associated with reorientation motion are also closer to experiment but discrepancies remain especially at high temperatures.