Gas and Particle Dynamics of a Contoured Shock Tube for Pre-clinical Microparticle Drug Delivery

We investigate the gas-particle dynamics of a device designed for biological pre-clinical experiments. The device uses transonic/supersonic gas flow to accelerate microparticles such that they penetrate the outer skin layers. By using a shock tube coupled to a correctly expanded nozzle, a quasi-one-dimensional, quasi-steady flow (QSF) is produced to uniformly accelerate the microparticles. The system utilises a microparticle “cassette” (a diaphragm sealed container) that incorporates a jet mixing mechanism to stir the particles prior to diaphragm rupture. Pressure measurements reveal that a QSF exit period – suitable for uniformly accelerating microparticles – exists between 155 and 220 mus after diaphragm rupture. Immediately preceding the QSF period, a starting process secondary shock was shown to form with its (x,t) trajectory comparing well to theoretical estimates. To characterise the microparticle, flow particle image velocimetry experiments were conducted at the nozzle exit, using particle payloads with varying diameter (2.7–48 μm), density (600–16,800 kg/m³) and mass (0.25–10 mg). The resultant microparticle velocities were temporally uniform. The experiments also show that the starting process does not significantly influence the microparticle nozzle exit velocities. The velocity distribution across the nozzle exit was also uniform for the majority of microparticle types tested. For payload masses typically used in pre-clinical drug and vaccine applications (≤ 1 mg), it was demonstrated that payload scaling does not affect the microparticle exit velocities. These characteristics show that the microparticle exit conditions are well controlled and are in agreement with ideal theory. These features combined with an attention to the practical requirements of a pre-clinical system make the device suitable for investigating microparticle penetration into the skin for drug delivery.     

Splitting,merging and spanwise wavenumber selection of Dean vortex pairs

Splitting, merging and spanwise wavenumber selection are studied during the initial development of Dean vortex pairs in a channel with mild curvature, an aspect ratio of 40, and an inner to outer radius ratio of 0.979. Two types of splitting events, and four types of merging events are evident from flow visualizations at Dean numbers from 75 to 220. These events are described in detail along with observations that occurrances of these different events are tied to spatial and temporal variations of spanwise wavenumbers of vortex pair spacing. Also discussed are frequency spectra of different events, recurrent phenomena, and the part played by splitting and merging in laminar to turbulent transition in curved channels.This study was sponsored by the Propulsion Directorate, U.S. Army Aviation Research and Technology Activity-AVSCOM, NASA-Defense Purchase Request 030030-P. Professor C. S. Subramanian provided assistance in setting up the traversing system and data acquisition systems used for this study. Mr. R. E. Hughes assisted in obtaining some of the results presented.     

Mechanism and origins of regio- and enantioselectivities in RhI-catalyzed hydrogenative couplings of 1,3-diynes and activated carbonyl partners: intervention of a cumulene intermediate

The mechanism of the rhodium-catalyzed reductive coupling of 1,3-diynes and vicinal dicarbonyl compounds employing H(2) as reductant was investigated by density functional theory. Oxidative coupling through 1,4-addition of the Rh(I)-bound dicarbonyl to the conjugated diyne via a seven-membered cyclic cumulene transition state leads to exclusive formation of linear adducts. Diyne 1,4-addition is much faster than the 1,2-addition to simple alkynes. The 1,2-dicarbonyl compound is bound to rhodium in a bidentate fashion during the oxidative coupling event. The chemo-, regio-, and enantioselectivities of this reaction were investigated and are attributed to this unique 1,4-addition pathway. The close proximity of the ligand and the alkyne substituent distal to the forming C-C bond controls the regio- and enantioselectivity: coupling occurs at the sterically more demanding alkyne terminus, which minimizes nonbonded interaction with the ligand. A stereochemical model is proposed that accounts for preferential formation of the (R)-configurated coupling product when (R)-biaryl phosphine ligands are used.     

Improving Physical Properties via C?H Oxidation: Chemical and Enzymatic Approaches

Physicochemical properties constitute a key factor for the success of a drug candidate. Whereas many strategies to improve the physicochemical properties of small heterocycle‐type leads exist, complex hydrocarbon skeletons are more challenging to derivatize because of the absence of functional groups. A variety of C H oxidation methods have been explored on the betulin skeleton to improve the solubility of this very bioactive, yet poorly water‐soluble, natural product. Capitalizing on the innate reactivity of the molecule, as well as the few molecular handles present on the core, allowed oxidations at different positions across the pentacyclic structure. Enzymatic oxidations afforded several orthogonal oxidations to chemical methods. Solubility measurements showed an enhancement for many of the synthesized compounds.     

MEXIT: Maximal un-coupling times for stochastic processes

Classical coupling constructions arrange for copies of the same Markov process started at two different initial states to become equal as soon as possible. In this paper, we consider an alternative coupling framework in which one seeks to arrange for two different Markov (or other stochastic) processes to remain equal for as long as possible, when started in the same state. We refer to this “un-coupling” or “maximal agreement” construction as MEXIT, standing for “maximal exit”. After highlighting the importance of un-coupling arguments in a few key statistical and probabilistic settings, we develop an explicit MEXIT construction for stochastic processes in discrete time with countable state-space. This construction is generalized to random processes on general state-space running in continuous time, and then exemplified by discussion of MEXIT for Brownian motions with two different constant drifts.     

A Tabu-Search Hyperheuristic for Timetabling and Rostering

Hyperheuristics can be defined to be heuristics which choose between heuristics in order to solve a given optimisation problem. The main motivation behind the development of such approaches is the goal of developing automated scheduling methods which are not restricted to one problem. In this paper we report the investigation of a hyperheuristic approach and evaluate it on various instances of two distinct timetabling and rostering problems. In the framework of our hyperheuristic approach, heuristics compete using rules based on the principles of reinforcement learning. A tabu list of heuristics is also maintained which prevents certain heuristics from being chosen at certain times during the search. We demonstrate that this tabu-search hyperheuristic is an easily re-usable method which can produce solutions of at least acceptable quality across a variety of problems and instances. In effect the proposed method is capable of producing solutions that are competitive with those obtained using state-of-the-art problem-specific techniques for the problems studied here, but is fundamentally more general than those techniques.     

A survey of surface mount device placement machine optimisation: Machine classification

The optimisation of a printed circuit board assembly line is mainly influenced by the constraints of the surface mount device (SMD) placement machine and the characteristics of the production environment. This paper surveys the characteristics of the various machine technologies and classifies them into five categories (dual-delivery, multi-station, turret-type, multi-head and sequential pick-and-place), based on their specifications and operational methods. Using this classification, we associate the machine technologies with heuristic methods and discuss the scheduling issues of each category of machine. We see the main contribution of this work as providing a classification for SMD placement machines and to survey the heuristics that have been used on different machines. We hope that this will guide other researchers so that they can subsequently use the classification or heuristics, or even design new heuristics that are more appropriate to the machine under consideration.