This document discusses the basic principles of green chemistry. It summarizes that green chemistry aims to make chemical processes and products more environmentally friendly and sustainable. A combination of factors is making green chemistry increasingly important in both the short and long term. These factors include rising costs of energy and waste processing, limited petroleum resources, and new legislation regulating chemicals. The document provides examples of green chemistry principles and technologies that can be applied throughout a chemical product's lifecycle from raw materials to end of life. It also discusses metrics for quantifying the environmental impact of chemical processes and comparing the greenness of alternative routes.

1. Chemical Technology
Basic Principles of Green Chemistry
A combination of existing and new drivers makes it more likely
that Green Chemistry will become increasingly important in the
short term, and essential in the longer term.
By Professor James H. Clark and Dr Paul Smith, Clean Technology Centre,
Department of Chemistry, University of York
Professor James Clark has an international reputation for his work in Green Chemistry and is a Founding Director of
the Green Chemistry Network. He was the founding Scientific Editor of the world’s leading journal in the field, Green
Chemistry, and is also an author of numerous books on the subject. He now holds the Chair of Industrial & Applied
Chemistry at York University (UK), and heads the Clean Technology Centre which integrates Green Chemistry research,
industrial collaboration and educational developments and issues relevant to the public understanding of science. He is
also the Director of the Greenchemistry Centre of Industrial Collaboration. Professor Clark’s research interests include
heterogeneous catalysis and supported reagents and the exploitation of renewable resources. He has won medals
and other awards for his research from the RSC, SCI, RSA and the EU.
Dr Paul Smith, BSc CChem FRSC, is currently the Commercial Manager of the Greenchemistry Centre of Industrial
Collaboration based at York University (UK). He gained his first degree in Chemistry from the University of
Nottingham (UK) and his PhD from the University of Cambridge (UK). His background is Chemical Development in
the pharmaceutical industry, having worked for over 20 years at GlaxoSmithKline. The major focus of his work was
to ensure that initial high quality supplies of potential new drug candidates were rapidly made available and that
subsequent manufacturing routes would be developed in a safe, robust, efficient, cost-effective and environmentally
sound manner. He also led a ‘Green Team’ which promoted Green Chemistry within the company.
Green Chemistry is the universally accepted term to REACH and other new legislation is also likely to bring
describe the movement towards more environmentally many consumer product related chemicals to the public’s
acceptable and sustainable chemical processes and attention, and we have often seen how even the
products (1). It encompasses education and promotional suggestion of a health or environmental-related problem
work, as well as research and commercial application of
Alternative feedstocks
cleaner technologies – some old and some new (2). (minimising petrochemicals)
Pre-Manufacturing
Waste minimisation
While Green Chemistry is widely accepted as an essential (in mining and refining)
development in the way that we practice chemistry, and is Solvent substitution (avoiding VOCs)
vital to sustainable development, its application has been Alternative routes/reduced
fragmented and represents only a small fraction of today’s number of process steps
chemical education and chemical manufacturing. However, Manufacturing Catalysis (especially heterogenisation)
a combination of existing and new drivers now makes it Intensive processing
more likely that it will become increasingly important in the
short term, and essential in the longer term. These drivers Alternative energy sources
include the increasing proportion of process costs due to
Degradable packaging
energy and waste, availability and cost issues for traditional Product Delivery
petroleum-based feedstocks, and perhaps most significantly Precious metal catalyst (etc) rental
the dramatic increase in legislation affecting chemical
production, storage, use and disposal. Product Use
Safer chemicals
Environmentally benign chemicals
In Europe, REACH (Registration, Evaluation, Biodegradable products
Assessment of Chemicals) will come into force this
decade and will undoubtedly be the most important End of Life Recyclable products
chemicals-related legislation in living memory (3). Its
‘Benign-by-design’
effects are as yet unclear, but conservative estimates
suggest that about 10% of existing chemicals will Figure 1: Application of clean technologies for Green Chemistry
become restricted, prohibitively expensive or unavailable. throughout the life-cycle of a chemical product
94 Innovations in Pharmaceutical Technology

2. Figure 2: Biomass as an alternative feedstock for the chemical industry Figure 3: Lactic acid as a platform molecule
OH
Corn starch Glucose
Petroleum
CO2H
Biomass Platform Molecules
CO2H
O OH
Chemical Plastics OH
Products O n O
O
can result in media-induced public alarm and over- imidazolium tetrafluoroborate (BMiMBF4) (10). Numerous
reaction by retailers. Social as well as environmental and examples of their use in the research literature are
economic drivers will force change in chemical available, many of which also involve catalysis (Figure 4).
manufacturing which will require a shift in emphasis
on chemistry research and education. This is being Some reactions can be carried out in the absence of solvent
encouraged by a number of organisations (4). and are often accelerated using microwave activation – a
methodology which shows considerable promise for the
GREEN CHEMISTRY IN THEORY future, especially with the availability of commercial
reactors including continuous flow systems. A number of
The principles of Green Chemistry should be applied other novel reactor technologies – often based on intensive
at all stages in the life-cycle of a chemical product, and processing such as microreactors – are also expected to
key technologies have been identified to help achieve become increasingly important. For example, we have
this (Figure 1). recently described catalytic microreactors and catalytic
spinning disc reactors (12) for high-throughput, safer and
Over 90% of organic chemicals in current use are more flexible chemical processing, which combines state-
derived from petroleum. A truly sustainable industry will of-the-art reactor technology with the latest examples of
require a shift towards renewable feedstocks (5). Biomass heterogeneous catalysis using mesoporous solid supports
can be better utilised in chemical manufacturing especially useful for liquid phase organic reactions.
both to provide building blocks and (close to) final
products (Figure 2). The ‘platform molecule’ concept is At the product end of the life-cycle, ‘benign by design’
particularly interesting since it provides a range of useful has an especially important significance since the
synthetic intermediates which are both more functional product should not cause harm to its users nor harm the
and more valuable than conventional petroleum-based environment when it is released. While maximising
feedstocks, and also simple enough to allow us to build reusability and recyclability of component parts are
up a wide range of important products. One example of important goals, some inevitably does get into the
this is lactic acid which is readily derived from the
fermentation of corn starch (Figure 3) (6). Figure 4: Examples of non-VOC solvent-based organic reactions
Much of the Green Chemistry research effort and most
Zn, NH4Cl, water
of the good case studies of Green Chemistry at work are PhNO2 PhNH2
associated with chemical manufacturing (7). The
substitution of volatile organic solvents is an important
+ CO + H2 Rh/scCO2
target for almost all chemical manufacturers – both in CO2R
OHC
CO2R
reactions and in work-ups and product purifications (2).
A number of alternative reaction solvents have been
O H
proposed, including water (8), volatile supercritical CO2 OH
alcohol
(9) which is easily removed by a drop in pressure, + H2
dehydrogenase/ BMiMBF4
R R
and non-volatile ionic liquids such as butylmethyl
Innovations in Pharmaceutical Technology 95

3. environment and rapid biodegradation to innocuous legislation will force an increasing emphasis on products,
breakdown species is the final green chemistry goal in the but it is also important that these in turn are manufactured
product’s life-cycle. by green chemical methods – and that the advantages
offered by Green Chemistry can be quantified. Legislation
GREEN CHEMISTRY IN PRACTICE or supply-chain pressures may persuade a company that the
use of a chlorinated organic solvent is undesirable, but how
There are now enough examples of Green Chemistry at can it select a genuinely ‘greener’ alternative? How can a
work in commercial processes that we can illustrate its company add environmental data to simple cost and
application across the product life-cycle (Figure 5) (2, 7). production factors when comparing routes to a particular
We must not, however, get complacent at these successes compound? Can the environmental advantages of using a
since they only represent step-change improvements in a renewable feedstock compared with a petrochemical be
tiny fraction of industrial chemistry worldwide. quantified? In order to make Green Chemistry happen, we
need to see the concept mature from an almost
We continue to use diminishing, polluting and philosophical belief that it is the ‘right thing to do’, to one
increasingly expensive fossil feedstocks for most chemical which can give hard, reliable data to prove its merits.
manufacturing. Hazardous reagents – including
aluminium chloride and chromates along with volatile These needs, together with a ‘reality check’, have led to
organic compounds such as dichloromethane – continue the emergence of Green Chemistry related metrics. The
to dominate chemical processing. Products continue to ultimate metric can be considered to be life-cycle
be designed based on cost and effort with little assessment (LCA) (16), but full LCA studies for any
consideration given to fate. particular chemical product are difficult and time-
consuming. Nonetheless, we should always ‘think LCA’ –
We must continue to innovate and design new processes if only qualitatively – whenever we are comparing routes
and products but – just as importantly – we need to learn or considering a significant change in any product supply
to more quickly adopt the new cleaner technologies if we chain. Green Chemistry metrics (17, 18) are most widely
are to achieve the triple bottom line of an economically, considered when comparing chemical process routes,
environmentally and socially effective industry (13). including limited – if easy-to-understand – metrics such
as atom efficiency (how many atoms in the starting
However, the uptake of Green Chemistry by the materials end up in the product) and attempts to
pharmaceutical industry is particularly encouraging and measure overall process efficiency such as E Factors
this is well illustrated by the success seen in the US (amount of waste produced per kg product).
Environment Protection Agency’s (EPA) prestigious
annual Presidential Green Chemistry Challenge (14). As with LCA, these metrics have to be applied with clear
For example, Bristol Myers Squibb won the Alternative system boundaries, and it is interesting to note that for
Synthetic Pathways Award in 2004 for the development process metrics these boundaries generally do not include
of a green synthesis for the manufacture of Taxol® via feedstock sources or product fate. Energy costs and water
plant cell fermentation and extraction. consumption are also normally not included, although –
given the increasing concerns over both of these – it is
Industry alone cannot be expected to discover and develop difficult to believe that they can be ignored for much
the novel green chemistry methods and technologies that longer. We propose that process efficiency metrics such as
are still needed. The good news is that, in the UK, E factor can be improved by including the CO2 equivalent
university research is becoming more focused on industry’s of the energy used in the process when calculating the total
needs – a good example being the recent setting-up of the waste for that process. At the product end of the life-cycle
Greenchemistry Centre of Industrial Collaboration, which we are used to testing for human toxicity, but we will
is based at the University of York (15). also need to pay more attention to environmental impact
and, here, measures of biodegradability, environmental
GREEN CHEMISTRY METRICS persistence, ozone depletion and global warming potential
are all important metrics.
In its short history, Green Chemistry has been heavily
focused on developing new, cleaner, chemical processes Last, but not least, we are moving towards applying
using the type of technologies described here. Increasing Green Chemistry metrics to feedstock issues. As we seek
96 Innovations in Pharmaceutical Technology

4. Figure 5: Examples of Green Chemistry in practice
Polymer – Clay
Specific processes nanocomposites as flame
(e.g. Ibuprofen, cyclohexanone) retardants (electronics
Biosynthesis of lactic Degradable
acid (Cargill Dow) manufacturers?) Polyethylene
(Symphony)
PLA
Green Chemistry
(Cargill Dow)
process metrics
(GSK) Biodegradable
chelant (Octel)
Product
Pre-manufacturing Manufacturing Product Use End of Life
Delivery
Clean pharmaceutical
Chitin (crabshell) synthesis (several Catalyst rental
based adsorbents companies) (Johnson Matthey)
Supercritical
(Carafiltration) carbon dioxide
for hydrogenation
(Thomas Swan)
Solid acids in Friedel Crafts reactions
(Rhodia, UOP, Contract Catalysts)
‘sustainable solutions’ to our healthcare, housing, food, 7. Lancaster M. Green Chemistry, an introductory
clothes and lifestyle needs, so we must be sensitive to the text, RSC, Cambridge, 2002.
long term availability of the raw materials that go into the
supply chain for a product. With increasing financial 8. Tsukinoki T and Tsuzuki H (2001), Green Chemistry, 37.
and legislative pressures from the feedstock and product
ends, and increasing restrictions and controls on the 9. Hu Y, Chen W, Banet Osuna AM, et al.
intermediate processing steps, chemistry must get greener! (2001). Chem Comm, 725.
The authors can be contacted at 10. Eckstein M, Filho MV, Liese A and Kragl U
jhc1@york.ac.uk and paulsmith@greenchemcic.co.uk (2004). Chem Comm, 1084.
References 11. Jackson T, Clark JH, Macquarrie DJ and Brophy JH
(2004). Green Chemistry, 2, 6, 193.
1. Anastas PT and Warner JC. Green Chemistry; Theory
and Practice, University Press, Oxford, 1998. 12. Vicevic M, Jachuck RJJ, Scott K et al. (2004).
Green Chemistry, 6, 533
2. Clark JH and Macquarrie DJ. Handbook of Green
Chemistry and Technology, Blackwell, Oxford, 2002. 13. Clark JH in: Green Separation Processes,
A Crespo Ed. Wiley, Chichester, 2005.
3. Warhurst AM (2002). Green Chemistry, 4, G20; see
also www.europa.eu.int/comm./enterprise/ 14. www.epa.gov/greenchemistry/presgcc.html
chemicals/chempd/reach/explanatory-note.pdf
15. www.greenchemcic.co.uk
4. www.chemsoc.org/gcn; www.gci.org;
www.rsc.org/greenchem 16. Graedel TE. Streamlined Life Cycle Assessment,
Prentice Hall, New Jersey, 1998.
5. Stevens CV and Vertie RG, Eds, Renewable
Resources, Wiley, Chichester, 2004. 17. Constables DJC, Curzons AD and Cunningham
VL (2002). Green Chemistry, 4, 521.
6. Clark JH and Hardy JJE in: Sustainable Development
in Practice, Azapagic A, Perdan S and Clift R, Eds. 18. Nüchter M, Ondruschka B, Bonrathard W and
Wiley, Chichester, 2004. Gum A (2004). Green Chemistry, 6, 128.
Innovations in Pharmaceutical Technology 97