1.1 Introduction
The pharmaceutical
industry is a multi-billion dollar operation in which companies compete
with each other to bring new or more effective drugs to consumers. Generic drug
companies use established drug patents to mass produce their own versions of
current drugs.
While most of us know
this, we may not know much about the chemistry behind the pharmaceutical
industry. In the push to produce drugs, chemical formulas have been developed
through the years that yield a little bit of drug while producing a lot of
wasteful by-products in the chemical process. When generic companies start
using these same chemical formulas, they leave behind even more waste because
of the scale of production.
2.1 Green Chemistry
Pharmaceutical companies of all types
have started thinking more about green chemistry. Green chemistry is the design
of chemical products and processes that reduce or eliminate the use or
generation of hazardous substances in all steps of particular synthesis or
process. Green chemistry applies across the life cycle of a chemical product,
including its design, manufacture, use, and ultimate disposal. Green chemistry
is also known as sustainable chemistry.
Green chemistry prevents
pollution at the molecular level. It is a philosophy that applies to all areas
of chemistry, not a single discipline of chemistry. It also applies innovative
scientific solutions to real-world environmental problems. This results in
source reduction because it prevents the generation of pollution. It can reduce
the negative impacts of chemical products and processes on human health and the
environment. Green chemistry lessens and sometimes eliminates hazard from
existing products and processes. It also designs chemical products and
processes to reduce their intrinsic hazards.
Chemists and medicinal
scientists can greatly reduce the risk to human health and the environment by
following all the valuable principles of green chemistry. The most simple and
direct way to apply green chemistry in pharmaceuticals is to utilize
eco-friendly, non-hazardous, reproducible and efficient solvents and catalysts
in synthesis of drug molecules, drug intermediates and in researches involving
synthetic chemistry. Microwave synthesis is also an important tool of green
chemistry by being an energy efficient process.
During the twentieth
century, chemistry changed the way people lived. And the greatest perceived
benefits came from pharmaceutical industries with development of organic
medicinal molecules. Pharmaceutical chemistry encompasses major chemicals,
reagents, solvents, catalysts and almost all type of organic reactions for
synthesis of active pharmaceutical molecules. Herein, many chemicals and
chemical processes are very hazardous, toxic and may have adverse effects on
the environment and on human health. Industries associated with pharmaceuticals
and fine chemicals are employing much more complex chemistry and produce
relatively much more waste, which is not at all suitable for environment and
nature.
During the early 1990's the
US Environmental Protection Agency (EPA) coined the phrase Green Chemistry to
promote innovative chemical technologies that reduce or eliminate the use or
generation of hazardous substances in the design, manufacture and use of
chemical products. Green chemistry is designed to reduce or eliminate negative
environmental impacts such that the use and production of chemicals may involve
reduced waste products, non-toxic components, and improved efficiency. Green
chemistry is not a particular set of technologies, but rather an emphasis on
the design of chemical products and processes. This approach offers
environmentally beneficial alternatives to more hazardous chemicals and
processes, and thus promotes pollution prevention.
2.1.1
Principles of Green Chemistry
Green chemistry is a highly effective
approach to pollution prevention as it applies innovative scientific solutions
to real-world environmental situations. The following 12 principles of Green
Chemistry provide a way for chemists to implement green chemistry.
The first is prevention of
waste. It is better to prevent waste than to treat or clean up waste after it
has been created. Second is atom economy.
Synthetic methods should be designed to maximize the incorporation of all
materials used in the process into the final product. Third is less hazardous
chemical syntheses which is synthetic methods should be designed, wherever
practicable, to use and generate substances that possess little or no toxicity
to human health and the environment. Fourth is designing safer chemicals. Chemical
products should be designed to achieve their desired function while minimizing
their toxicity.
The fifth principle is
safer solvents and auxiliaries. Unnecessary use of auxiliary substances (e.g.,
solvents, separation agents, etc.) should be avoided wherever possible and made
innocuous when used. The sixth principle is design for energy efficiency. Energy
requirements of chemical processes should be recognized for their environmental
and economic impacts and should be minimized. If possible, synthetic methods
should be conducted at ambient temperature and pressure. The seventh principle
is use of renewable feed stocks. Whenever technically and economically
practicable, raw material or feedstock should be renewable rather than depleting
it.
The eighth principle of
green chemistry is reduce derivatives. Unnecessary derivatization (use of
blocking groups, protection/ deprotection, temporary modification of
physical/chemical processes) should be minimized or avoided if possible, because
such steps require additional reagents and can generate waste. The ninth
principle is catalysis which catalytic reagents (as selective as possible) are
superior to stoichiometric reagents. The tenth principle is design for degradation.
Chemical products should be designed so that at the end of their function they
break down into innocuous degradation products and do not persist in the
environment.
The eleventh principle is
real-time analysis for pollution prevention. Analytical methodologies need to
be further developed to allow for real-time, in-process monitoring and control,
prior to the formation of hazardous substances. The last principle of green
chemistry is inherently safer chemistry for accident. Prevention substances and
the form of a substance used in a chemical process should be chosen so as to
minimize the potential of chemical accidents, including releases, explosions,
and fires.
3.1 Future Trends for Green Chemistry in
Pharmaceutical Industry
This is what will happen in this arena
over the next 20 years. The pharmaceutical industry has been accused in the
past of being ‘ ungreen ’ , but a reasoned observation will show that many of
the ideas and much of the drive to push for changes in synthetic methodology,
green chemistry, and engineering have come from certain groups and companies
within the pharmaceutical industry.
The
publication in 1992 of a table comparing E factors of various industry segments
raised awareness of the high levels of waste generation in the pharmaceutical
industry. Initial efforts to explain this state of affairs highlighted as
complex products with demanding high quality standards, complexity of the
regulatory process and its requirements which can slow down process changes and
relatively low-volume products compared with other industry segments.
However, there was a
realization that the various industry segments were actually in the order that
would be expected, that is, pharmaceutical industry in general should produce more
waste per kilo that the fine chemical industry , which in turn should produce
more waste than the bulk chemical industry because of issues of molecular
complexity and synthesis length. The target for each industry segment should be
improved and, ideally, move up to the next level.
It
is clear that if these aspirational E factor targets are to be met, then
improvements are desirable in many areas of chemistry, including waste
minimization in medicinal chemistry, greener synthetic methods in primary manufacture,
increased use of chemo and biocatalysis, and more collaborative efforts between
pharmaceutical companies. These areas are all discussed in the remainder of
this chapter.
3.1.1 Waste Minimization in Drug Discovery
Green Chemistry in the pharmaceutical
industry first flourished in chemical development or process research
departments. However, in the last few years there has been a back integration
of Green Chemistry into medicinal chemistry itself. This is not without its
challenges, as the modern practice of drug discovery relies heavily on speed of
execution, which in turn relies on robust methodologies emphasizing broad
applicability and reliability rather than environmental impact. In a large
pharmaceutical company only about 5% of the chemical waste is produced in its
drug discovery operations, but the advantage of greening these small - scale
operations is that this improved chemistry will then be available for the
scaling up of the chemistry as the drug moves through the development process.
In 2004 Pfizer started an influential program to reduce its use of chlorinated
solvents with initial focus on dichloromethane due to its relatively high
volume use in medicinal chemistry.
In 2008 the program was
extended to include chloroform usage. Some research chemistry sites had
completely eliminated the use of chloroform at this time, but two sites
continued to have high usage. An intensive education program was put in place
by the Pfizer Green Chemistry Network leading to a dramatic reduction in chloroform
usage during 2008. One of the benefits of this type of change is that once the
education program has been put in place and a change in behaviour has been
made, the company then receives the benefit of those behavioural changes ever
afterwards. In the view of the three editors of this book, dichloromethane is
an essential solvent in the drug discovery process but needs to be used
responsibly, and its use should be minimized. In contrast, we look forward to
the day when chloroform disappears completely from the modern drug discovery
laboratory.
A
similar picture is emerging from some medicinal chemistry groups in Astra-
Zeneca (AZ). Opportunities for improving environmental performance are often
identified using lean sigma principles. Often highlighted is the use of large
amounts of undesirable solvents like n - hexane and dichloromethane in the
separation of mixtures and purification rather than in reactions. Initiatives
that are under way include replacement of n - hexane with isohexane or heptane
(both of which are significantly less toxic), eliminating the use of solvents
such as carbon tetrachloride and chloroform, and minimizing the use of
dichloromethane. Often this has involved moving away from silica as the
traditional stationary phase in column chromatography. The goal is to move
toward greener solvents without compromising on speed, quality, and delivery of
drug development projects.
Other
examples of greener technology being adopted by medicinal chemistry are the use
of supercritical CO 2 chromatography in place of traditional normal and reverse
phase chromatography, especially in the analysis and preparative separation of
enantiomers. A move towards automation and flow chemistry also offers both
green and business benefits, such as increased speed of materials delivery and
safe access to chemistries considered too unsafe to use in traditional batch
mode in a standard synthetic organic chemistry laboratory. Another example of
good practice widely adopted within AZ medicinal chemistry groups to minimize
materials consumption is the use of bar coding and electronic tracking of
laboratory chemicals. This maximizes the use of any chemical ordered, and, if
used correctly, minimizes chemical inventory. Another initiative within
medicinal (and process) chemistry groups focuses on saving energy by optimizing
the use of fume hoods – often the biggest consumers of energy in an R & D
establishment.
3.1.2 Greener
Synthetic Methods in Primary Manufacturing
The case histories in this text
provide vivid examples of how much has been achieved in the past decade with
the ‘greening’ of syntheses in the pharmaceutical industry. However, two recent
surveys highlighted the fact that great scope for future work remains, and
presented fascinating insights into the types of reaction carried out during
drug development programs. A Pfizer survey examined the reactions carried out
over a 17 - year period in a single pilot plant, providing a view of the
changes over that timescale, while a study from the process chemistry groups of
AZ, GSK, and Pfizer gave a snapshot of the chemistry used to synthesize 128
active pharmaceutical ingredient s (API s). Both of these surveys revealed the
widespread use of both atom inefficient functional group transformations and
older stoichiometric synthetic methods such as Friedel - Crafts acylations,
halogenations, and metal hydride reductions.
The principles of Green
Chemistry are currently most often applied to the redesign of API processes
late in the development timeline or even post regulatory approval. Ideally, the
principles of Green Chemistry should be incorporated into API manufacturing
process design as early as possible in development. As the vast majority of
APIs for patent - expired products are manufactured using processes developed without
green chemical insights, the development of green processes for drugs
manufactured by generic companies represents a great opportunity for
innovation.
3.1.3 Alternative
Solvents in the Pharmaceutical Industry
Solvents represent the biggest
contributor to the life cycle impact of pharmaceutical agents and the potential
for harm to the environment during the manufacturing process. Data from the
Swedish regulator, KEMI, suggest that global solvent demand is growing by ∼ 2% per year, but the use of chlorinated
and hydrocarbon solvents is dropping – in the case of certain chlorinated
materials, very rapidly. This is partly due to legislation and partly due to
green chemistry initiatives (voluntary restraint). Most pharmaceutical
companies now have solvent reduction initiatives that are focused on developing
more efficient processes (synthetic sequences) that involve less solvent use,
more solvent recovery, and a rational choice of solvents to minimize any
environmental impact. Over the past 30 years or so, a number of ‘greener’
alternatives to volatile solvents have been proposed.
3.1.3.1 Water
Water is cheap, relatively abundant in
many part of the world, safe, and, when pure, environmentally benign. It
is also true that some reactions show unusual selectivity and/or rate
enhancements when run in, or more accurately, on water. However, a closer
examination of many reactions ‘in’ water reveals that in fact one or more
liquid reagents have been used in large excess, so they are in fact biphasic
reactions. There is also a misguided perception that water, after use as a
reaction medium, can be ‘poured down the drain’. On an industrial scale, there
can be a considerable cost and environmental burden associated with remediation
of waste water streams contaminated with solvents and organic and metal
residues.
One not obvious advantage
of water is the use of water/detergent mixtures to clean chemical
reactors/plant. Preparation of chemicals to GMP standard requires extensive and
rigorous cleaning protocols. In a production plant, up to 30% of total solvent
inventory is utilized in cleaning. If water/detergent cleaning can be used,
this can save up to 90% of the solvent used for cleaning.
3.1.3.2
Ionic Liquids (ILs)
Over the past ten years, ILs have
moved out of the realm of academic study and are being used in a diverse range
of industrial processes. It is true to say that the application of ILs in the
synthesis of pharmaceuticals and fine chemicals has been hampered by much ‘
green wash ’ and focus on single - issue sustainability claims such as that ILs
are better than all other solvents because they have essentially no vapour
pressure and are not classified as volatile organic compound s (VOC s). Other
factors limiting take-up have been the lack of ecotoxicity and life cycle
impact, cost, and recycle or disposal procedures at end of life. For scientists
engaged in route design and manufacture of pharmaceuticals it has been clear
for a long time that a process that ran efficiently in ethanol or ethyl acetate
would never be improved in an environmental or commercial sense by replacing
such solvents with an IL. This has somewhat detracted from the search for areas
in which the application of ILs could impart real benefits to the chemistry and
process.
3.1.3.3
Fluorous Solvents
High - molecular - weight
polyfluorinated materials used in ‘ fluorous phase ’ techniques have poor life
cycle impacts, and the high environmental impact of heavily fluorinated
materials is now becoming apparent, so it is unlikely that this technology will
have much impact on greening pharmaceutical manufacture. Of course fluorous
technologies may, however, be of interest and use to the medicinal chemist
working on a small scale to facilitate the rapid separation of catalysts from
products.
3.1.3.4 Molecular Solvents from Renewable Sources
A number of solvent - like materials
can be derived from renewable bio resources, but these tend to be more highly
oxygenated than conventional solvents, and this has several ramifications. They
are not suitable for wide ranges of chemical reactions because of their higher
reactivity and viscosity, and higher boiling points can add an energy penalty
in their use and recovery. Nevertheless, some are displacing solvents commonly
used in synthesis. 2-Methyltetrahydrofuran has many favourable properties that
make it a good solvent for organic synthesis, and, being derived from
agricultural waste products (C - 5 sugars), it has a much better life cycle
impact than tetrahydrofuran, which is derived from oil.
Of course, a number of
solvents in common use in the chemical industry, such as ethanol, acetic acid,
and ethyl acetate, can be derived from either bio or oil raw materials. The
debate rages over the life cycle impact of bio versus fossil fuel ethanol. A
further complication in this area is the societal question of corn versus
lignocellulosic ethanol, and indeed the use of any food crop, arable land, or
fertilizers to provide solvents or other bio renewable consumer products in
place of food products.
3.1.3.5
Solid - Phase Reactions
A range of reactions have been
reported which take place between two solids under the influence of mechanical
agitation such as ball milling. A reasonably large range of reaction types has
been reported. Concerns over homogeneity and reproducibility at scale plus
process safety aspects of the control of exothermic reactions may mean that
this technology could only be of interest in a very limited number of cases.
3.1.3.6 Obstacles
to Change
We all want to become more sustainable
and ‘green’, so why has there not been a great rush into these ‘greener’
alternatives? For a number of scientific and business reasons, progress and
change in this area will be cautious and measured. Some have been touched on in
earlier chapters but are worth recapping here.
First, lack of both
environmental and mammalian toxicity data on new solvent systems. This becomes
much more of a problem when solvents are used toward the end of a synthetic
route and may contaminate the API. Inevitably there will be no regulatory
guidance from the International Conference on Harmonization (ICH) on
permissible levels in API. This represents a big regulatory barrier to making
any change to existing registered processes or being the first to use a novel
solvent in a final stage or API crystallization. Mammalian toxicity data is
prohibitively expensive for most solvent manufacturers to obtain for new
solvents.
Cost is also one of the
problems. Governments, healthcare providers, and generic competition are
putting pressure on ethical pharmaceutical suppliers to reduce the cost of
medicines. Solvents that are produced on a small scale for niche markets will
probably be expensive. While the production of pharmaceuticals is currently
solvent intensive, the pharmaceutical industry is some way off being the
biggest user of solvents. Historically, new solvents being adopted by the
pharmaceutical industry that are available in bulk at reasonable cost have not
been designed for organic synthesis, but have been developed for much bigger
markets where economies of scale reduce manufacturing costs. An excellent
example is provided by petroleum octane enhancers such as t - butyl
methyl ether and 2-methyltetrahydrofuran. Security of supply which sourcing a
novel solvent from a single supplier represents a high degree of risk for a
launched product.
4.1 Conclusion
The pharmaceutical industry has made a
major contribution to both the life expectancy and the quality of life of the
human population, but it is clear that these contributions must be made without
major detriment to the environment. In this book we have tried to capture some
of the major achievements in moving to a greener pharmaceutical industry, and
in general the performance to date has been good. However, there are many
challenges and opportunities that remain outstanding. In our view the scope for
innovation and improvement remains as wide as ever.
Referrences
