Chemistry & Life Sciences

Green Chemistry Metrics for the Fine Chemical, Pharmaceutical and Related Industries

06.03.2014 -

At The Source - Waste has been an issue in the chemical industry for many years, but the approach to waste has changed significantly over that period. Twenty-five to 30 years ago the focus was on end-of-pipe solutions to reduce the pollution characteristics of the waste generated. In recent years the emphasis has shifted to reducing waste at the source by designing processes and syntheses that produce minimal waste.

One of the key factors in this change was Roger Sheldon's 1992 article in Chem. Ind. on the E Factor (kilogram of waste produced per kilogram of product), where he divided the chemical industry into four main sectors (see table 1) and looked at the amount of kilograms of waste generated per kilogram of product for each sector.

Table 1: Waste generation in the chemical industry

Industry sector

Product tonnage

E Factor (kg waste per kg product)

Oil refining

106-108

~0.1

Bulk chemicals

104-106

<1-5

Fine chemicals

102-104

5-50

Pharmaceuticals

101-103

25-100+

 

This was a real wake-up call for the pharmaceutical and fine chemical sectors to take urgent action. It resulted in the development of a whole series of metrics to get a handle on how much waste was being generated and be able to show improvements over time. Green chemistry metrics are mainly based on mass, but some are based on energy usage, environmental toxicity and ozone depletion potential, for example. However, the metrics most commonly quoted in the literature are based on mass, solvent usage and energy, according to "Green Chemistry Metrics: Measuring and Monitoring Sustainable Processes," A. Lapkin and D.J. Constable (Eds), and "Green Chemistry in the Pharmaceutical Industry," P.J. Dunn, A.S. Wells and M.T. Williams. This has arisen because of the need to develop metrics that are simple to measure, easy to use, and easy to sell to senior management, with this last point being particularly important.

 

The two main metrics based on mass are the E Factor and process mass intensity (PMI, mass of all materials used in the product/mass of product, as described by W.J. Watson in Green Chem. in 2012). The difference between the E Factor and PMI is subtle, and in mathematical terms the relationship is:

E Factor = PMI - 1.

 

The main difference is that producing less waste reduces the E Factor, whereas using less raw material reduces PMI, but this also leads to a reduction in the amount of waste generated. The two advantages of PMI are that it is easy to sell to senior management - we will reduce our raw material usage, which saves costs - and it is very simple to use. Every chemist should note down the materials used in a given chemical preparation and the amount of product produced, the two figures needed to calculate PMI. (This is available automatically in some electronic lab notebooks.) The E Factor requires the measurement of the amount of waste produced. The ongoing discussion as to whether water should be included in the calculations is common to both E Factor and PMI.

 

Typically in fine chemicals and pharmaceuticals the main component in any synthesis is the solvent, and so not surprisingly solvent usage and the number of solvents required are commonly used metrics. Solvent recycling can reduce the amount of solvent that must be purchased by more than 50%, but this normally requires distillation to purify the waste solvent before reuse. We are also encouraged to reduce energy usage by avoiding high and very low temperatures. Metrics related to energy usage are difficult to measure or calculate directly because most chemical manufacturing sites contain a large number of multipurpose plant vessels, as well as laboratories and offices. It is rare that the measuring equipment is in place such that individual unit operations can be measured. Software packages such as Batch Plus can calculate energy usage, however some unit operations are bound to be more energy-intensive than others, such as heating at reflux and distillation, which requires energy for heat of vaporization as well as cooling the vapors. So simple metrics such as the number and length of reflux operations, the number of distillations and the amount of time can be used as an indirect measure of energy usage.

 

One of the problems we sometimes face is balancing different aspects of our process, such as energy usage versus waste generation, for two process options. In some cases, as with the biocatalytic process for manufacturing pregabalin, the answer is straightforward (see Scheme 1). The energy usage for the version of the process where the unwanted enantiomer is recycled is higher than the version without recycle, but this is outweighed by the reduced requirement for the starting cyano-diester (4) and the cost of disposing of (R)-4.

 

Scheme 1: Biocatalytic route to pregabalin (from "Green Chemistry in The Pharmaceutical Industry," P.J. Dunn, A.S. Wells and M.T. Williams [eds], Wiley-VCH, 2010)

In other cases the decision usually comes down to cost, for example when comparing processes for amide formation (see Scheme 2) carried out at CABB AG.

Scheme 2: Options for amide formation (from J. Schrikel, presentation at Hazardous Chemistry for Streamlined Large Scale Synthesis conference, Cologne, in November)

A comparison of the energy usage and waste generation for the two routes is given in Table 2.

Table 2: Comparison of waste generation and utility requirements for amide formation processes

Metric

Route 1

Route 2

Electricity

100%

75%

Steam

100%

71%

Atom efficiency

53.1%

45.3%

PMI

4.3

12.2

E Factor

2.2

11.3

Route 1 is more energy-intensive than route 2, but route 1 is chemically more efficient as measured by atom efficiency, PMI and E Factor - particularly as the SO2 and HCl byproducts from acid chloride formation are recycled.

 

We really need a metric that measures or compares overall process efficiency, which will include not only PMI, E Factor, waste generation and energy usage but will also include a comparison of how a given process operates in different types of reactors. A number of green chemistry metrics can be easily collected and used to assess individual process steps or the overall synthesis of a given product or even the whole portfolio of a company's product - as well as measuring progress over time in terms of a company's "green performance." However, the challenge now is to measure the greenness of the engineering aspects of chemical processes and develop an integrated metric to cover chemistry and engineering.