The Problem
High throughput screening is a standard method used in drug discovery for testing potential active ingredients and also for conducting bio-assays. A major programme of research in pharmaceutical companies is aimed at miniaturising the assay systems so that they can operate on micron dimension samples to reduce the amount of material required and so speed up the overall drug discovery process. This work includes the development of micron scale equipment for fluid handling and for detection. An essential feature of these developments is the modelling of fluid flow in such micron scale systems.
The Challenge
Conventional fluid dynamics codes are not applicable to microfluidic modelling because, inter alia, the assumption of zero velocity at the wall is invalid. Daresbury computational science and engineering group turned their attentions to this generic problem in 1999 when the ‘Centre for Microfluidics and Microsystems Modelling’ (C3M) was established. The resulting modular code (µTHOR) has been proved in numerous applications from bubble transport to microchannel flow modelling in complex geometries. In particular, the development of microassay systems depends critically on the leading edge capability of µTHOR to simulate a wide range of geometries and material properties and hence to identify designs that operate effectively in ultra high throughput processes.
The Solution
C3M has performed computational microfluidic dynamics simulations on the proposed assay systems across a wide range of design parameters, including flow rates, channel dimensions, intersection geometries, fluid properties and reagent concentrations. This has extended to areas such as mixers, pumps, electro-kinetic and magneto-hydrodynamic transport, two-phase flow and design optimisation. This has been critical in identifying design preferences and thereby focusing the experimental developments. The success of the approach has led to the design of biosensing microtitre plates which permit up to 1536 screening assays to be performed simultaneously, compared with just four using current technology, and leading to massive acceleration of the drug discovery process.
Electric field strength in x-direction
Stream function contours
The Benefits
- The ability of µTHOR to accommodate both geometric designs and the physical properties of the fluid materials in combined simulations allowed the modelling of complete devices in operation
- The successful modelling of a wide range of device structures and operating conditions significantly reduced the experimental programme with attendant cost savings in the research project
- The ability to construct massively parallel bio-assay devices will deliver both significant cost savings and reduced candidate identification times in drug discovery programmes.
The problem
Powdered titanium dioxide (or titania) is used widely as a pigment and in other applications. Titania exists naturally as one of three crystalline phases (or polymorphs): rutile, anatase and brookite. Made by the ‘chloride’ process, it is critically important to achieve a specific mean particle size and distribution to optimise the product’s light scattering properties. The process involves a high temperature (1500-2100K) flame reactor in which gaseous titanium tetrachloride combines with gaseous oxygen to produce titanium dioxide and chlorine gas. Practical studies have empirically linked temperature and the use of additives to particle size effects and phase stability. However, these studies are limited by their inability to unravel the competing effects of the three sub-processes, nucleation, growth and coagulation.
The challenge
A detailed understanding of the sub-processes was required if the complex reactor environment was to be modelled successfully. Using computer simulation techniques it is possible to isolate the effects of the three sub-processes. The current poor insight into the atomic processes underlying the bulk behaviour is a limitation in other possible simulation approaches such as computational fluid dynamics (CFD). The possibility to develop such parameters using molecular dynamics (MD) modelling of the sub-processes was a major challenge for this investigation, aimed at understanding the fundamentals linking optimal reaction conditions to powder phase, particle size and distribution.
The solution
The Daresbury MD code DL-Poly was used to study the thermodynamic, structural and transport properties of micro-clusters of rutile titania at a range of temperatures typical of the chloride process - the first time that this had ever been attempted. Simulations were performed on 1245 atom clusters between 1000 and 3000K. Rutile was shown to be the stable phase and the coagulation process was shown to be long timescale (ns) and markedly influenced by surface ion diffusion. Atoms at or near the surface exhibited high diffusion rates, which is important in cementing particles together. The temperature dependence of coagulation observed experimentally is not found in the simulation for pure rutile nanoclusters. This strongly suggests an involvement of chlorine adsorption and desorption on the titania clusters leading to their observed ‘stickiness’ in the manufacturing process.
Molecular simulation of micro-clusters of rutile titania
The benefits
- The customer has gained a unique insight into the fundamental chemistry of a complex process which indicates a vital area for further study into the thermochemistry of chlorine adsorption and desorption on titania clusters
- The originality of the simulation on ceramic nanoclusters has potential benefits in modelling the more general process of powder sintering by which powders are fused to create a solid mass at high temperatures and pressures