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ACS Sustainable Chemistry & Engineering Perspective (AE) and the E factor, are the simplest and most popular green metrics. AE is a theoretical number which assumes the use of exact stoichiometric quantities of starting materials and a theoretical chemical yield and disregards substances, such as solvents and auxiliary chemicals which do not appear in the stoichiometric equation. The strength of AE, and what its critics tend to forget, is that it can be applied without the need for experimentation. This makes it an extremely useful tool for rapid prediction and evaluation of the amounts of waste that will be generated in alternative routes to a particular target molecule. The E factor, in contrast, is the actual amount of waste produced in the process and takes waste from all auxiliary components, for example, solvent losses and chemicals used in workup, into account. Another difference is that AE is applied to individual steps, but the E factor, on the other hand, can easily be applied to a multistep process thus facilitating a holistic assessment of a complete process. A higher E factor means more waste and, consequently, greater negative environmental impact. The ideal E factor is zero, perfectly in line with the first of the 12 Principles of Green Chemistry: “It is better to prevent waste than to treat or clean up waste after it is formed”. It can be calculated, for a particular product, manufacturing site, or even a whole company, from a knowledge of the number of tons of raw materials purchased and the number of tons of product sold. Importantly, lower E factors correlate well with reduced manufacturing costs of APIs since they are a direct reflection of lower process materials input, reduced costs of hazardous and toxic waste disposal, improved capacity utilization, and reduced energy demand. In short, there are strong economic incentives for the pharmaceutical industry to integrate green chemistry into the entire process research, development, and manufacturing life cycle.21 Originally, waste was defined as “everything but the desired product”. However, water was excluded based on the rationale that including it would result in a skewing of E factors. Thus, an otherwise “clean” process that used substantial amounts of water could appear to have more environmental impact than an alternative process, generating copious amounts of waste but using much less water. On the other hand, in many cases, disposal or reuse of the water would involve some sort of pretreatment, which argues for including it in the waste generated. Indeed, the current trend in the pharmaceutical industry is to include water in the E factor, and in an assessment of a biocatalytic process for an advanced intermediate for atoravastatin (Lipitor), we calculated the E factor both with and without water.22 A major source of waste in chemicals manufacture, particularly in the pharmaceutical industry, is solvent losses. Thus, an inventorization of waste formed in pharmaceuticals manufacture revealed that solvents and water accounted for 58% and 28%, respectively, of the process waste compared to 8% for the raw materials.23 More recently, the use of simple E factors (sEF) and complete E factors (cEF), depending on the stage of development of the process, has been suggested.23 The sEF does not take solvents and water into account and is more appropriate for early route scouting activities, whereas the cEF accounts for all process materials including solvents and water, assuming no recycling, and is more appropriate for total waste stream analysis. The true commercial E factor will fall somewhere between the sEF and cEF and can be calculated when reliable data for solvent losses are available. D Another major cause of the high E factors of processes for the manufacture of APIs is their high molecular complexity and the correspondingly large number of chemical steps needed for their assembly from commercially available starting materials. Hence, there is a definite need for step-economic syntheses as advocated by Wender and co-workers.24 In the Green Aspiration Level (GAL) concept,23 the complexity of processes is taken into account, using a combination of Wender’s step economy and Baran’s process ideality metric,25 in order to compare the E factor of a particular process to the industry norm as derived from the inventorization of routes to various APIs. Indeed, one way to enhance the greenness of multistep syntheses is to integrate several catalytic steps into step economic, one-pot procedures.26 Such “telescoping” of multi- step syntheses has numerous benefits: it avoids the need for isolating and purifying intermediates, it involves fewer unit operations, requires less solvent and reactor volume, and affords shorter cycle times, higher volumetric and space−time yields, and less waste (lower E factors). Moreover, coupling of reactions can drive equilibria toward product and avoid the need for excess reagents. A higher E factor means more waste and, consequently, greater negative environmental impact. The ideal E factor is zero, in line with the goal of zero waste manufacturing plants. It can be calculated, for a particular product, production site, or even a whole company, from a knowledge of the number of tons of raw materials purchased and the number of tons of product sold. Importantly, lower E factors, since they are a reflection of lower process materials input, reduced costs of hazardous and toxic waste disposal, improved capacity utilization and reduced energy demand, correlate well with reduced manufacturing costs of APIs. In short, there are strong economic incentives for the pharmaceutical industry to integrate green chemistry into the entire process research, development, and manufacturing life cycle. The AE and E factor concepts have motivated both industrial and academic chemists globally to explicitly consider waste generation, in addition to the more common criteria such as synthetic convergence, chemical yield, and cost of goods, when designing a synthesis of a target molecule. Furthermore, in the past decade, the E factor and AE concepts have been incorporated into chemistry text books27 and chemistry curricula at both university18,19,28,29 and high school levels.30 Other Mass-Based Metrics. A variety of alternative mass- based metrics have been proposed16−20 for measuring the greenness of processes. They can be divided into two groups: those representing a percentage of the ideal analogous to AE and those based on kg/kg analogous to the E factor (Scheme 3). An example of the former is reaction mass efficiency (RME),31,32 a refinement of AE taking yield and use of excess reagents into account, that was proposed by Constable and co- workers at GSK. Similarly, carbon economy is the mass of carbon in the product divided by the total mass of carbon in the reactants, expressed as a percentage.31 Effective mass yield (EMY) is the mass of desired product divided by the mass of nonbenign reagents and was proposed by Hudlicky and co- workers.33 The problem with applying this metric is to define a “nonbenign reagent”. An example of the latter type is mass intensity (MI), defined as the mass ratio of total input of materials (excluding water) to final product, that is MI = E factor + 1.31,32 The Green Chemistry Institute Pharmaceutical Round Table adopted this DOI: 10.1021/acssuschemeng.7b03505 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXXPDF Image | Metrics of Green Chemistry and Sustainability
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