Chemistry & Industry 13 September 201024

Applying green chemistry principles earlier in the drug development process could dramatically

reduce the environmental impact of pharmaceuticals manufacture, Nitesh Mehta reports

Encouraging 'enviropreneurship'

Green chemistry

Green chemistry

25Chemistry & Industry 13 September 2010

• Pharma industry manufacturing processes generate 25 to 100 times more waste by weight than active pharmaceutical ingredient (API)

• Around 25–100 kg of effluent is produced/kg of API, which poses a big challenge for manufacturers and is a potential threat to water security

• Green chemistry technologies can reduce the ratio of waste generated, and slash the Environmental Impact (E) Factor of multi-step manufacturing processes

• Green chemistry is inherently economical and often improves product yields, while at the same time reducing waste and saving effluent treatment costs

In Brief

Worldwide, 1bn kg of active pharmaceutical ingredients (APIs) are currently being manufactured annually. To manufacture these APIs, on average seven to eight chemistry steps are involved and the average efficiency of the entire manufacturing process – in terms of the final product yield – ranges from 20 to 30%. The amount of waste generated by this process is staggering: weight for weight, 25 to 100 times more waste is produced, compared with the amount of API made, which gives pharmaceuticals the highest Environmental Impact (E) Factor of any chemicals manufacturing industry (Table 1).

Most pharmaceutical manufacturing processes generate huge quantities of liquid wastes that can’t be recycled back into the process for fear of carryover of impurities to the finished product, which may breach stringent quality standards. For every kg of API synthesised, around 25–100 kg of effluent is produced, with a chemical oxygen demand of 10,000 to 1m and often comprising complex organic heterocyclic molecules, many of which have not been characterised and measured. These molecules directly or indirectly end up in our lakes, rivers, streams and seas and biodegrade very slowly, posing a huge challenge and a threat to our water security. According to a recent US Geological Survey study, for example, outflows from two New York wastewater treatment plants that receive more than 20% of their wastewater from pharmaceutical facilities had concentrations of pharmaceuticals that were 10–1000 times higher than outflows from other plants nationwide that did not receive watewater from pharma plants (C&I 2010, 13, 13).

Environmental standards in pharma vary across the world. But as environmental awareness grows, regulatory bodies are tightening the rules governing discharge of any kind of effluents. Within a short time, we expect to see standards in Asia as stringent as those in the West.

Indian firm Newreka Green-Synth Technologies, which offers green chemistry based solutions, was started in 1997 by a group of technocrats from the Indian Institute of Technology (IIT-Bombay). We like to consider ourselves operating ‘enviropreneurs’, in other words we identify environmental challenges, do invention and innovation through numerous experiments in the laboratory to create an alternative technology and offer it as a ‘complete solution’ – from lab scale development to scale-up to commercialisation – to our customers.

Green chemistry is inherently economical. If a process doesn’t improve economics, it is not green chemistry. For example, if we increase the conversion and selectivity of a process using a new catalyst, the yield of the process improves and the costs of manufacturing decreases. This also directly leads to lesser amount of wastes, saving effluent treatment costs.

Ultimately, the objective is to reduce the customer’s E-factor and grow our customer’s environmental and economic competitiveness by:• developing and commercialising alternative technologies for chemistries like reduction, nitration, acetylation and diazotisation-hydrolysis;

• developing and commercialising recycle solutions such that acidic, neutral, alkaline or solvent streams generated from any process can be recycled back to the same process. This concept is called ‘Recycle at Source’; and• entering in to long term partnerships with our customers to ultimately transform their entire molecule synthesis to be ‘green’.The E-Factor concept was developed by Roger A. Sheldon, professor of biocatalysis and organic chemistry at Delft University of Technology in the Netherlands in the late 1980s and is today just one of a number of metrics to measure the environmental footprint of a process or a product.

Scientists and organisations around the world are still debating on which of these metrics is the most effective. However, E-Factor turns out to be very useful because of its simple definition and the ease with which it can be calculated for any process or product.

At Newreka, our 50-strong team of chemists and chemical engineers conduct more than 40 experiments daily. We are in the process of creating a system whereby researchers will be calculating the E-Factor for every experiment in the lab. This would allow researchers to keep track, and continuously measure the environmental impact, of the process they are developing, and their progress towards the target E-Factor.

We believe that for new molecules, the right time to start exploring green chemistry is while they are in the Phase II or Phase III trials. During the preclinical or early phase of drug development, the number of molecules is high and it is not possible to find green chemistry routes for all them. Out of these large numbers of molecules, very few molecules move in to Phase II and Phase III trials. By the time these molecules move in to Phase IV and commercialisation, the process is already frozen and locked once the Drug Master File (DMF) is submitted to the regulatory authorities. Hence, during Phase IV and commercialisation is too late to explore alternative green chemistry based manufacturing processes. Exploring green chemistry during Phase II and Phase III trials is therefore more practical and would ensure that the manufacture of our next generation of drugs is environmentally benign.

The other category of molecules where there is a huge opportunity to explore green chemistry processes are generics and ‘potential’ generics, where drug patents are about to expire. During the development phase of a new molecule, pharma companies are in a rush to commercialise, so that they can make the most of the time available before patent expires. Hence, most of the time, the processes filed with regulators during launch are synthetic chemistry based processes where the E-Factor is very high.

Hence, for molecules that are already off-patent or are going to go off-patent in the next five years, there is a huge scope to reduce the E-Factor. These also offer a big opportunity to develop green chemistry processes because:• When a molecule goes generic, the volumes drastically increase. The effluent volumes also increase proportionally; data by Sheldon showed pharma companies generate 50-100+ lbs waste/lb of product. Disposal of such huge quantities of waste becomes a big challenge;

Table 1: Pharma has the highest environmental impact (E) Factor Source: R A Sheldon

'Green chemistry is inherently economical. If a process doesn’t improve economics, it’s not green chemistry'

Sector E - Factor Product Tonnage

Oil Refining < 0.1 106 - 108

Bulk Chemicals 1 – 5 104 – 106

Fine Chemicals 5 – 50+ 102 – 104

Pharmaceuticals 25 – 100+ 0 - 103

Green chemistry

26 Chemistry & Industry 13 September 2010

• When a molecule goes generic, competition increases. This leads to a drastic reduction in its price, shrinking pharma company margins. Green chemistry processes improve economic competitiveness, and hence the possibility of sustaining profitability.

Around four years ago, one of the fastest growing pharma companies in India approached Newreka to work on one of its molecules. This antiretroviral drug prevents the transfer of virus from a HIV infected mother to the child in the womb, thereby helping to reduce the number of HIV positive babies being born.

The firm wanted us to develop a green chemistry based process for the first four steps of this molecule, all of which were very polluting and also hazardous. The first step was a diazotisation-hydrolysis generating huge quantities of high acidic effluents. The second was a nitration, generating huge quantities of highly acidic effluent containing sulphuric – nitric mixture. The third was a chlorination, again generating chlorine containing acidic effluent, red in colour. The fourth step was a high pressure and exothermic hydrogenation using pyrophoric catalyst like Raney Ni and methanol as a solvent. Safety was the biggest concern for this step.

Our customer’s synthetic chemistry process for these four steps together had an E-Factor of 175: it produced 175lb of waste/lb of intermediate manufactured. As the volumes of these intermediates started touching 120t/year, managing such huge quantities of highly acidic waste (175 x 120 = ca 20,000t/year) started to become a challenge. Also, there was ongoing pressure to supply antiretroviral drugs at lower prices, hence the firm’s margins were shrinking.

So, the reasons this pharma company approached us were:• To reduce the reduce E-Factor;• To improve economic competitiveness; and• To develop an inherently safer process.

Inside of an exclusive partnership, over a couple of years, we developed green chemistry processes for all the four steps to reduce the E-Factor from 175 to 17 – a 90% reduction. In addition, the customer’s yield for that intermediate improved by 250%. We didn’t change the route of synthesis; we developed an alternative process by working on the following three aspects:• Exploring new catalysts and reducing agents that are inherently safe and more selective;• Optimising the process by working on raw material consumptions, process parameters, etc; and• Recycling at source by reintroducing the reaction or extraction medium, generated after isolation of the intermediates at various stages, back to the same process.

This was the first time that we partnered with

a pharma company to develop and commercialise a green chemistry and green engineering based process for the entire manufacturing process of a pharma intermediate or drug. The objective was to make the entire synthetic chemistry based process ‘greener’. Currently, we are in the final stage of negotiations with one of the largest pharma companies in India for one of its molecules for which it intends to scale-up manufacturing capacity to 100t/year. The company is conscious about the environmental footprint of its manufacturing operations and hence intends to reduce its E-Factor before expanding production capacities for the molecule.

Every pharma company could benefit from green chemistry approaches. Existing synthetic chemistry processes offer huge scope to improve economic and environmental competitiveness. The gap between theoretical yield and the yield achieved by using synthetic chemistry processes is huge. The raw material consumptions are much higher than theoretical requirements and the potential of catalysis is largely unexplored.

Globally, however, the challenge of effluent pollution is far bigger than any one company or group can tackle alone. What is needed is an approach that is non-linear and has the potential to give exponential results. At Newreka, we would like to expand our model of ‘enviropreneurship’ beyond the confines of our own laboratory space and create an environment where entrepreneurs

globally take on an environmental challenge, create a solution for that problem, offer that solution to society or industry and in the process generate business and profits.

What we are proposing is encouraging chemists and chemical engineers around the world – including young students just out of college – to take on being ‘enviropreneurs’. If we can create such an ecosystem then it may become possible to work on and develop solutions simultaneously for thousands of environmental challenges at a time. Creating such an ecosystem will require seed capital from governments and/or private investors, establishing an IP system to protect their ideas, technical assistance and other resources to transform the enviropreneur’s idea into a commercially viable solution.

At a time when clean water is emerging as key challenge for sustainability of human activity on the planet, effluents from the pharma API industry are a matter of serious concern. The problem can either be treated as threat or it can be turned into opportunities for chemists and chemical engineers to find new solutions based on the principles of green chemistry and green engineering.

Nitesh H. Mehta is founder and director of Newreka Green-Synth Technologies, based in Goregaon (East), Mumbai, India.

'During the development phase of a new molecule, pharma companies are in a rush to commercialise…Hence, most of the time, the processes filed with regulators during launch are synthetic chemistry based processed where the E-Factor is very high'

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Green chemistry: promises to clean up pharmaceutical sector