Chemistry in a parallel world

Martyn Deals explores parallel chemistry – its origins and its future The origins of Parallel Chemistry can be traced back to the early 1990s, when the pharmaceutical industry in particular was looking for new and improved ways of going about the drug discovery process. New drug molecules were becoming harder and harder to discover. The traditional process of ‘one-at-a-time’ analogue synthesis for making these molecules had been employed for many years, but it was time consuming and highly labour intensive, hence there was a strong desire to find a more efficient way. The idea of Combinatorial Chemistry, together with high through-put screening (HTS) was put forward, whereby huge numbers (thousands or even millions) of potential new drug molecules could be made and tested in a fraction of the time required by the traditional method. This involved a change from traditional solution phase chemistry techniques to a methodology termed Solid Phase Chemistry, where for ease of handling, to facilitate isolation and some degree of purification of the required molecule, chemistry was performed on a solid material, typically a small polystyrene bead, or particle of silica. Over a period of several years, a lot of time and effort was put into developing and delivering this concept, with the use of laboratory automation and robotics and large numbers of molecules were made by Combinatorial Chemistry. A range of instruments were specifically developed for undertaking automated chemistry in this way, by for example; Advanced Chemtech, Argonaut, Tecan, Bohdan and Zinsser. However it quickly became apparent that the difficulty in getting anything more than the most basic chemistry to work on the solid phase, together with limitations of the purification process (a simple filtration and washing) meant that the quality of molecules being produced was not good enough. Furthermore, the highly corrosive and hazardous nature of a many of the reagents involved placed great demands on the instruments and as a result many of them failed to become accepted mainstream synthesis solutions. As a result, solid phase chemistry and the Combinatorial Chemistry concept rapidly fell from favour. However, the basic concepts of performing more than one process at a time was a sound one and there was considerable interest in applying this to more traditional solution phase techniques, to make it easier to get the chemistry to work; and on smaller, more realistic numbers of compounds which would allow traditional chromatographic purification techniques to be employed. Exploring these possibilities resulted in what we now refer to as Parallel Chemistry. The term ‘Parallel Chemistry’ has evolved over the last 10 to 15 years as technologies and the requirements of the chemist in the lab have changed; and has come to mean different things to different people. However, in simple terms, it refers to any application where more than one chemical procedure is performed at the same time, on a single piece of apparatus. Generally the term is applied to synthesis, but this can be extended to include the wider process of synthesis, work-up and purification. This can range from anything between two or more reaction vessels being treated at the same time on a stirring hotplate, to the processing of much larger numbers of reactions (24, 48 or 96) in what are commonly termed ‘chemical libraries’. For parallel synthesis to be truly useful as a technique, it is essential that the normal parameters required for carrying out traditional ‘one-at-a-time’ chemistry are available for each of the parallel reactions, so the ability to control temperature accurately between -70°C and +180°C, stir the reactor contents and work under an inert gas atmosphere is of high importance. One area where parallel chemistry is commonly employed is in the generation of chemical libraries, where it is beneficial to create more than one molecule at a time for SAR (Structure Activity Relationship) screening. Typically a group of molecules relating to a common structural class can be made, by varying the functionality around a common core molecule. In this case the reactants vary between reaction vessels, but generally other parameters, such as solvents, catalysts and operating parameters such as temperature and stirring remain constant. Another important application for parallel synthesis is in reaction optimisation, where the chemist is trying to improve a given reaction; for example to increase the yield, or to reduce the formation of an unwanted impurity. Here the reactants in each reaction vessel will generally be the same, whilst other factors such as solvent, catalyst or temperature will be varied. DOE (design of experiment) is often used in such situations, to select the best combination of variable parameters to be investigated. The main driver for the development of Parallel Chemistry has been the requirement for increasing productivity, whilst at the same time increasing the quality of information obtained. Making and screening more compounds gives a better chance of finding the best compound; screening more reaction conditions gives a better chance of finding a better, or the best, one. Parallel Chemistry apparatus specifically designed and developed to do this efficiently also typically offer the benefits of reduced cost and space requirements, along with improved control of reaction conditions from one reaction to the next, compared with simply duplicating conventional laboratory apparatus. Fumehood space in a laboratory is always at a premium, so maximising this space is obviously of great importance. The ability to perform multiple reactions and processes in roughly the same footprint that would previously have been required to perform a single reaction is therefore an attractive proposition. The desire to perform Parallel Chemistry was heavily championed within the pharmaceutical and agrochemical industries. However chemists found there was no suitable equipment available to buy ‘off-the-shelf’ – it simply hadn’t been invented yet! It was therefore left to the pioneering chemists and engineers from within these companies, such as GSK, Pfizer, Monsanto, Roche and AstraZeneca to define what they required and develop and build the equipment themselves. It soon became clear to the chemists that the way to progress the technology was to partner with specialist laboratory instrument suppliers to take the ideas and prototypes they were developing and refine them into robust, reliable and commercially available products that chemists could buy ‘off-the-shelf’. This led to a host of parallel synthesis products from companies such as Argonaut, Mettler, Bohdan, HEL, J-Kem and Radleys coming onto the market at much the same time. All were aimed at delivering Parallel Chemistry, but with subtle variations dependent on the priorities of the inventors. Many of these products had a short lifetime and quickly disappeared from the marketplace. The successful ones, which have continued to develop and improve, remain available today. Typically, these were the most robust and easiest to use, whilst at the same time offered to meet the widest range of practical tasks that the chemist would wish to perform. In many cases the more obvious or simple the parallel concept, the more widely adopted the technology. Indeed the ability to demonstrate increased productivity by processing multiple reactions through the processes of synthesis, work-up or purification without the requirement for extensive training of the chemist was the key. We live in an ever changing world where the desire to do things faster, more cost-effectively and efficiently is always present and new technologies are constantly being developed to allow this to happen. Things are no different in chemistry, particularly in the world of the pharmaceutical industry and drug discovery. Recent years have seen the arrival of techniques such as microwave synthesis and continuous flow synthesis, which have certainly had an impact. Microwave Synthesis allows the application of high levels of energy to a chemical reaction and for this to be done simply at above ambient pressures. A combination of these factors has been demonstrated to allow the synthesis of molecules more rapidly than traditional heating technologies. However, care must be taken to identify the exact conditions, as rapid synthesis of a target molecule can quickly lead to rapid decomposition. Furthermore, microwave synthesis suffers from the problem of being limited in scale, because of the physical properties of the microwaves themselves and is therefore not always considered to be a generic technology. Continuous Flow Synthesis has more recently become established as an alternative method for undertaking chemistry in the laboratory. The ability to carefully control the flow and mixing together of reactants and reagents in a localised ‘mini reactor’, typically a piece of narrow bore chemically-resistant tubing, with very efficient heat transfer characteristics makes this a particularly attractive way of performing dangerous and highly exothermic reactions. The ability to infinitely vary both the size of the reactor (by changing the length of the tubing) and the reaction time (by changing the flow rate) makes this a completely scalable technology. However, to achieve the necessary control of reaction parameters to produce the desired results requires investment in sophisticated and expensive equipment (for example from Syrris, Uniqsis and Vapourtec). Current thinking is that to maximise on the investment required for this technology, it is best employed where it shows biggest benefits, e.g. for highly exothermic reactions. Will Parallel Chemistry continue to play a role alongside these new and future emerging technologies? The answer is almost certainly “Yes”! The simplicity, robustness and ease of use of the hardware presents minimal barriers to technology uptake and is a large part of the appeal. Its suitability to take on virtually any chemistry synthesis task and be able to replicate it in multiple reaction vessels will continue to offer high productivity gains, and a high value return on investment. The testament to the continued success of parallel chemistry is the continued adoption in all areas of chemistry research and development including Universities, Food and Beverage, Cosmetic, Textile, Environmental, Research Institutes, Petrochemical, Biofuels, Nuclear, Military, Contract Research, Chemical, Polymer, Agrochemical and of course Pharmaceutical research. Author Martyn Deals is R&D manager at Radleys, where he has responsibility for developing the next generation of Productivity Tools for Chemists.