Process R&D

When I left university after my PhD and started my career in industry as a development chemist, I encountered many applied aspects of my job that were completely new to me. And like most people in those days I learnt "on the job" gathering information and knowledge from my older, more experienced colleagues. But nevertheless I still made mistakes. Some years later in 1989/1990 I came across a course on chemical research and development that had just been developed by Dr Trevor Laird who had formed the company Scientific Update. Dr. Laird had been head of process research and development at Smith, Kline and French's Tonbridge site, but had the foresight to see that there was a real need for applied training for chemists and chemical engineers starting work in process research and development (R&D) to stop new entrants making the same mistakes as he had made when he started out.

From lab scale to large scale
There are many changes that can affect a reaction when it is scaled up, but one of the most significant is time and particularly mixing time. Mixing times typically change from a 1-2 seconds in the lab to 0.5-1 minutes on large scale. The result is that when one component is being added to a reaction there will be a significant difference between the local concentration at any one point in the reactor compared to the average concentration. Other average parameter / local parameter differences that also affect the reaction care temperature and pH either of which can affect the reaction selectivity and so the yield and purity of the isolated product.
Process R&D departments fulfil a vital role during the commercialization of new chemical products (pharmaceutical, agrochemical, flavour, fragrance etc). The key requirement is to devise a synthesis that can be operated safely and economically on production scale, but in addition they will often have to deliver batches of material (from a few hundred grams in the early stages to 100's of kilograms or even tonnes during later development) for further studies such as formulation, toxicity investigations, clinical trials for pharmaceuticals, field trials for agrochemicals, or further chemical transformations.
Converting a synthetic route used to make gram quantities of a chemical to a process for manufacturing tonne quantities is a topic about which much is known, but where the "tricks of the trade" are handed down within companies. There is little shared experience between chemists in different companies, and the result is a lack of awareness of what is involved in chemical development - the skills and techniques needed to efficiently scale-up chemical processes. Since many processes require chiral synthesis or use chiral catalysts, where control of conditions and optical purity are critical, the development chemist who transfers these processes to plant needs to be aware of the techniques which will lead to efficient scale-up.

Knowledge and new ideas
The training course on "Chemical Development and Scale Up in the Fine Chemical and Pharmaceutical Industries" that Dr. Laird developed gives an overview and introduction to the subject. The course consists of 14 lectures and 5 interactive problem sessions and concepts and techniques are illustrated by a wealth of real-life examples. The lectures are designed to cover all the main topics and are organized in a logical order to follow the pattern of a typical process/project.
The first topic is Route Selection. A review on the Costing of Chemical Processes follows and the course moves on to a detailed lecture on Development and Optimization. In this section approaches to improvement in the yield and selectivity of particular steps using standard chemical techniques is discussed along with studying the effect of changing the order of steps and/or telescoping two or more steps together. A lecture on Solvent Effects deals with the choice of solvent or solvent systems, but also discusses neoteric solvents such as ionic liquids, supercritical fluids, and fluorous solvents.
Statistical Methods of Optimization is an introduction to an alternative approach to the optimization of chemical reactions and processes. Methods covered include the Simplex Method, Modified Simplex Method, Factorial Design, Fractional Factorial Design, Path of Steepest Ascent, and Response Surface Modelling. A brief discussion of commercially available software packages is also included. In Analytical Issues in Chemical Process R&D quality issues are discussed. The main areas covered are sampling, methodology, specifications, impurity control, and finally quality assurance including Good Manufacturing Practice, Process Validation, and Quality by Design.
Work-up is arguably one of the most important topics since a significant amount of development time is spent on product isolation and purification. The lecture on The Importance of Work-Up discusses quenching reactions, filtration and product isolation. This leads in to An Appreciation of Chemical Engineering Principles which does not try to teach chemists to be chemical engineers but rather to show them the sorts of areas where their chemical engineering colleagues can help them solve problems or preferably to engineer them out before they occur. An interactive session dedicated to issues of heat transfer and mass transfer follows before thinking about how to approach the first pilot plant batch in "Planning For Scale Up".
"Crystallization and Polymorphism" also includes some discussion of salt forms and hydrates and solvates. "Chemical Development of Enantiomerically Pure Compounds" surveys the various approaches to producing single-enantiomer products concentrating on resolution/crystallization and asymmetric catalysis but also including some discussion on biocatalysis.
The final two topics are "Thermal Hazard Testing and Runaway Reactions" and "Waste Minimization and Effluent Control". "Thermal Hazard Testing and Runaway Reactions" contains an overview of testing equipment available for assessing thermal hazards of reactions and individual compounds as well as a discussion of problems that have encountered in the past and a discussion of which functional groups to beware of. "Waste Minimization and Effluent Control" is essentially about green chemistry issues. Participants are encouraged to think about the whole process when looking waste minimization and not just to think about individual reagents or yields, with the most efficient processes being those that generate the least waste.