An article on applying Green Chemistry principles earlier in the drug development process could dramatically reduce the environmental impact of pharmaceuticals manufacture.

1. Green chemistry
Encouraging
'enviropreneurship'
Applying green chemistry principles earlier in the
drug development process could dramatically
reduce the environmental impact of pharmaceuticals
manufacture, Nitesh Mehta reports
24 Chemistry & Industry 13 September 2010

2. Green chemistry
Worldwide, 1bn kg of active pharmaceutical
Sector E - Factor Product Tonnage
ingredients (APIs) are currently being manufactured
annually. To manufacture these APIs, on average Oil Refining < 0.1 106 - 108
seven to eight chemistry steps are involved and
the average efficiency of the entire manufacturing Bulk Chemicals 1–5 104 – 106
process – in terms of the final product yield –
ranges from 20 to 30%. The amount of waste Fine Chemicals 5 – 50+ 102 – 104
generated by this process is staggering: weight for
weight, 25 to 100 times more waste is produced, Pharmaceuticals 25 – 100+ 0 - 103
compared with the amount of API made, which
Table 1: Pharma has the highest environmental impact (E) Factor Source: R A Sheldon
gives pharmaceuticals the highest Environmental
Impact (E) Factor of any chemicals manufacturing
industry (Table 1). Scientists and organisations around the world are
Most pharmaceutical manufacturing processes
generate huge quantities of liquid wastes that
'Green chemistry still debating on which of these metrics is the most
effective. However, E-Factor turns out to be very
can’t be recycled back into the process for fear is inherently useful because of its simple definition and the ease
of carryover of impurities to the finished product, with which it can be calculated for any process
which may breach stringent quality standards. For economical. If a or product.
every kg of API synthesised, around 25–100 kg
of effluent is produced, with a chemical oxygen process doesn’t At Newreka, our 50-strong team of chemists
and chemical engineers conduct more than
demand of 10,000 to 1m and often comprising
complex organic heterocyclic molecules, many of
improve economics, 40 experiments daily. We are in the process of
creating a system whereby researchers will be
which have not been characterised and measured.
These molecules directly or indirectly end up in our
it’s not green calculating the E-Factor for every experiment in the
lab. This would allow researchers to keep track,
lakes, rivers, streams and seas and biodegrade chemistry' and continuously measure the environmental
very slowly, posing a huge challenge and a threat impact, of the process they are developing, and
to our water security. According to a recent US their progress towards the target E-Factor.
Geological Survey study, for example, outflows • developing and commercialising recycle We believe that for new molecules, the right
from two New York wastewater treatment plants solutions such that acidic, neutral, alkaline or time to start exploring green chemistry is while
that receive more than 20% of their wastewater solvent streams generated from any process can they are in the Phase II or Phase III trials. During
from pharmaceutical facilities had concentrations be recycled back to the same process. This concept the preclinical or early phase of drug development,
of pharmaceuticals that were 10–1000 times is called ‘Recycle at Source’; and the number of molecules is high and it is not
higher than outflows from other plants nationwide • entering in to long term partnerships with our possible to find green chemistry routes for all them.
that did not receive watewater from pharma plants customers to ultimately transform their entire Out of these large numbers of molecules, very few
(C&I 2010, 13, 13). molecule synthesis to be ‘green’. molecules move in to Phase II and Phase III trials. By
Environmental standards in pharma vary The E-Factor concept was developed by Roger the time these molecules move in to Phase IV and
across the world. But as environmental awareness A. Sheldon, professor of biocatalysis and organic commercialisation, the process is already frozen and
grows, regulatory bodies are tightening the rules chemistry at Delft University of Technology in locked once the Drug Master File (DMF) is submitted
governing discharge of any kind of effluents. the Netherlands in the late 1980s and is today to the regulatory authorities. Hence, during Phase
Within a short time, we expect to see standards in just one of a number of metrics to measure the IV and commercialisation is too late to explore
Asia as stringent as those in the West. environmental footprint of a process or a product. alternative green chemistry based manufacturing
Indian firm Newreka Green-Synth Technologies, processes. Exploring green chemistry during Phase
which offers green chemistry based solutions, was II and Phase III trials is therefore more practical
started in 1997 by a group of technocrats from the In Brief and would ensure that the manufacture of our next
Indian Institute of Technology (IIT-Bombay). We like generation of drugs is environmentally benign.
• Pharma industry manufacturing
to consider ourselves operating ‘enviropreneurs’, in The other category of molecules where there
processes generate 25 to 100 times
other words we identify environmental challenges, is a huge opportunity to explore green chemistry
more waste by weight than active
do invention and innovation through numerous processes are generics and ‘potential’ generics,
pharmaceutical ingredient (API)
experiments in the laboratory to create an where drug patents are about to expire. During the
alternative technology and offer it as a ‘complete development phase of a new molecule, pharma
• Around 25–100 kg of effluent is
solution’ – from lab scale development to scale-up companies are in a rush to commercialise, so that they
produced/kg of API, which poses a big
to commercialisation – to our customers. can make the most of the time available before patent
challenge for manufacturers and is a
Green chemistry is inherently economical. If expires. Hence, most of the time, the processes filed
potential threat to water security
a process doesn’t improve economics, it is not with regulators during launch are synthetic chemistry
green chemistry. For example, if we increase the based processes where the E-Factor is very high.
• Green chemistry technologies can
conversion and selectivity of a process using a new Hence, for molecules that are already off-
reduce the ratio of waste generated,
catalyst, the yield of the process improves and patent or are going to go off-patent in the next five
and slash the Environmental Impact
the costs of manufacturing decreases. This also years, there is a huge scope to reduce the E-Factor.
(E) Factor of multi-step manufacturing
directly leads to lesser amount of wastes, saving These also offer a big opportunity to develop green
processes
effluent treatment costs. chemistry processes because:
Ultimately, the objective is to reduce the • When a molecule goes generic, the volumes
• Green chemistry is inherently
customer’s E-factor and grow our customer’s drastically increase. The effluent volumes also
economical and often improves
environmental and economic competitiveness by: increase proportionally; data by Sheldon showed
product yields, while at the same time
• developing and commercialising alternative pharma companies generate 50-100+ lbs waste/
reducing waste and saving effluent
technologies for chemistries like reduction, lb of product. Disposal of such huge quantities of
treatment costs
nitration, acetylation and diazotisation-hydrolysis; waste becomes a big challenge;
Chemistry & Industry 13 September 2010 25

3. Green chemistry
• When a molecule goes generic, a pharma company to develop and
Photolibrary
competition increases. This leads to a commercialise a green chemistry and
drastic reduction in its price, shrinking green engineering based process for the
pharma company margins. Green entire manufacturing process of a pharma
chemistry processes improve economic intermediate or drug. The objective was
competitiveness, and hence the to make the entire synthetic chemistry
possibility of sustaining profitability. based process ‘greener’. Currently, we
Around four years ago, one of the are in the final stage of negotiations with
fastest growing pharma companies in one of the largest pharma companies in
India approached Newreka to work on India for one of its molecules for which
one of its molecules. This antiretroviral it intends to scale-up manufacturing
drug prevents the transfer of virus from capacity to 100t/year. The company
a HIV infected mother to the child in the is conscious about the environmental
womb, thereby helping to reduce the footprint of its manufacturing operations
number of HIV positive babies being and hence intends to reduce its E-Factor
born. before expanding production capacities
The firm wanted us to develop a green for the molecule.
chemistry based process for the first four Every pharma company could benefit
steps of this molecule, all of which were from green chemistry approaches. Existing
very polluting and also hazardous. The synthetic chemistry processes offer
first step was a diazotisation-hydrolysis huge scope to improve economic and
generating huge quantities of high environmental competitiveness. The gap
acidic effluents. The second was a between theoretical yield and the yield
nitration, generating huge quantities achieved by using synthetic chemistry
of highly acidic effluent containing processes is huge. The raw material
sulphuric – nitric mixture. The third was consumptions are much higher than
a chlorination, again generating chlorine theoretical requirements and the potential
containing acidic effluent, red in colour. of catalysis is largely unexplored.
The fourth step was a high pressure Globally, however, the challenge
and exothermic hydrogenation using of effluent pollution is far bigger than
pyrophoric catalyst like Raney Ni and any one company or group can tackle
methanol as a solvent. Safety was the alone. What is needed is an approach
biggest concern for this step. that is non-linear and has the potential
Our customer’s synthetic chemistry to give exponential results. At Newreka,
process for these four steps together had we would like to expand our model of
an E-Factor of 175: it produced 175lb of Green chemistry: promises to clean up pharmaceutical sector ‘enviropreneurship’ beyond the confines
waste/lb of intermediate manufactured. of our own laboratory space and create
As the volumes of these intermediates an environment where entrepreneurs
started touching 120t/year, managing such huge globally take on an environmental challenge,
quantities of highly acidic waste (175 x 120 = ca create a solution for that problem, offer that
20,000t/year) started to become a challenge. Also,
there was ongoing pressure to supply antiretroviral
'During the solution to society or industry and in the process
generate business and profits.
development phase
drugs at lower prices, hence the firm’s margins were
shrinking.
What we are proposing is encouraging chemists
and chemical engineers around the world – including
So, the reasons this pharma company of a new molecule, young students just out of college – to take on being
approached us were: ‘enviropreneurs’. If we can create such an ecosystem
• To reduce the reduce E-Factor; pharma companies then it may become possible to work on and
• To improve economic competitiveness; and
• To develop an inherently safer process. are in a rush to develop solutions simultaneously for thousands of
environmental challenges at a time. Creating such an
commercialise…
Inside of an exclusive partnership, over a couple
of years, we developed green chemistry processes
ecosystem will require seed capital from governments
and/or private investors, establishing an IP system to
for all the four steps to reduce the E-Factor from
175 to 17 – a 90% reduction. In addition, the
Hence, most of the protect their ideas, technical assistance and other
resources to transform the enviropreneur’s idea into
customer’s yield for that intermediate improved by time, the processes a commercially viable solution.
250%. We didn’t change the route of synthesis; At a time when clean water is emerging as key
we developed an alternative process by working filed with regulators challenge for sustainability of human activity on
on the following three aspects:
• Exploring new catalysts and reducing agents during launch are the planet, effluents from the pharma API industry
are a matter of serious concern. The problem can
that are inherently safe and more selective;
• Optimising the process by working on raw material
synthetic chemistry either be treated as threat or it can be turned into
opportunities for chemists and chemical engineers
consumptions, process parameters, etc; and
• Recycling at source by reintroducing the reaction
based processed to find new solutions based on the principles of
green chemistry and green engineering.
or extraction medium, generated after isolation of where the E-Factor is
the intermediates at various stages, back to the Nitesh H. Mehta is founder and director of Newreka
same process. very high' Green-Synth Technologies, based in Goregaon
This was the first time that we partnered with (East), Mumbai, India.
26 Chemistry & Industry 13 September 2010