Tools and techniques

Mass metrics

Metrics play a crucial role in guiding reaction development towards a greener process. By identifying potential issues at an early stages, it becomes possible to rectify these challenges before scale up, which would otherwise exasperate waste and safety issues.

The basis of a good metric in green chemistry is that it is clearly defined, simple, and it must stimulate informed actions. The following metrics describe material utilisation (and conversely waste) and are best applied to early stage, low volume chemistry. Later, combinations of more advanced measurements that incorporate energy use, environmental impact, hazard assessment, etc. will need to be introduced. This is elegantly organised in the framework designed by McElroy et al. (2015). 

Yield

The efficiency of a chemical process has traditionally been assessed primarily (and usually only) through yield. While yield effectively communicates the quantity of the final product derived from the limiting reactant, it fails to provide insights into other aspects of reaction efficiency, for example, the quantity of reagents, excess reactants, and solvents. Yield remains important because it is a measure of efficiency, and has a bearing on all other metrics that incorporate the mass of product as a variable. 

Atom economy

Atom Economy is the percentage obtained by dividing the molecular weight of the desired product by the total molecular weight of all substances contributing to the reaction as reactants (Trost, 1991). It does not factor in reaction yield or consider the stoichiometry of the reactants, or the quantity of auxiliary substances such as solvents. Yet it remains a useful guide to the inherent wastefulness of a reaction. The optimum Atom Economy is 100%, where all the atoms in the reactants are theoretically incorporated into the product (assuming quantitative yield).

E-factor

The E-factor represents the total mass of waste generated compared to the mass of the desired product(s) (Sheldon, 2017), In an ideal scenario, the E-factor would be zero.  However, the pharmaceutical industry relies on complex, multi-step chemistry requiring solvents and catalysts and other reagents that all contribute to waste. It is not uncommon for the E-factor of active pharmaceutical ingredient (API) manufacturing to be over 100.

Reaction mass efficiency

The pharmaceutical industry has been proactive in establishing and using mass-based metrics to understand waste from chemical reactions (Curzons et al. 2001). GlaxoSmithKline (GSK) pioneered the concept of reaction mass efficiency (RME), which quantifies the efficiency of a reaction by dividing the mass of the product obtained by the total mass of reactants (Jimenez-Gonzalez et al., 2011). RME goes beyond Atom Economy by incorporating the impact of both yield and the mass of excess reactants. An addition reaction occurring to completion between equimolar quantities of reactants has a RME of 1 (100%).

Process mass intensity

 The ACS Green Chemistry Institute Pharmaceutical Roundtable has embraced Process Mass Intensity (PMI) as its designated mass metric and has created an online tool to estimate PMI, aiding the design of more environmentally sustainable chemistry. PMI is defined as the total mass of materials required to produce a specified mass of product, encompassing reactants, reagents, solvents used in reaction and purification, and catalysts (Monteith et al., 2020). Ideally, PMI equals one, which represents zero waste and all materials integrated into the product. The preferential use of the PMI metric helps data comparison across companies to foster efficiency and sustainability throughout the supply chain, including potential outsourcing strategies. It should be noted that PMI is equal to E-factor + 1, so only one is necessary to describe a reaction.

Worked example: The PMI of the synthesis of bupropion hydrochloride

The following reaction is an example of the synthesis of bupropion (Andrew et al., 2022). Several optimisations have been made over the original synthesis. There is a PMI tool below to allow you to see the effect of making further changes to the molar excesses of the reactants and the number of water washes used in purification. This reaction is also the case study for the final quiz.

Use the PMI calculator above to complete the quiz regarding the synthesis of bupropion hydrochloride.