Pharmaceutical Green Chemistry: Is Just Green Chemistry or Is Something Else More?

J. Chem. Eng. Chem. Res. Vol. 1, No. 5, 2014, pp. 290-301 Received: June 30, 2014; Published: November 25, 2014 Journal of Chemical Engineering and C...
1 downloads 0 Views 362KB Size
J. Chem. Eng. Chem. Res. Vol. 1, No. 5, 2014, pp. 290-301 Received: June 30, 2014; Published: November 25, 2014

Journal of Chemical Engineering and Chemistry Research

Pharmaceutical Green Chemistry: Is Just Green Chemistry or Is Something Else More? Rui M. A. Pinto1,2 and Samuel M. Silvestre2,3 1. Department of Veterinary Medicine, Escola Universitária Vasco da Gama, Avenida José R. Sousa Fernandes, 197, Lordemão, 3020-210 Coimbra, Portugal 2. Centro de Neurociências e Biologia Celular, Universidade de Coimbra, 3004-517 Coimbra, Portugal 3. Health Sciences Research Centre, Faculdade de Ciências da Saúde, Universidade da Beira Interior, 6201-506 Covilhã, Portugal Corresponding author: Rui M. A. Pinto ([email protected]) Abstract: Classically, the chemistry involved in drug synthesis uses traditional methods which in turn lead to less environmentally friendly processes. In recent years, however, pharmaceutical chemistry has been undertaken an important approach to the principles of Green Chemistry. This paper introduces the concept of pharmaceutical green chemistry, which covers activities in the fields of drug discovery and chemical process development, under the paradigm of green chemistry. More than just applying the principles of green chemistry, this new concept directs the pharmaceutical chemist for a commitment with the final goal of delivery medicinal products within the context of meeting the current standard of living. Key words: Green chemistry, pharmaceutical green chemistry, atom economy, E-factor, chemical process.

indicate that the destruction of local flora associated

1. Introduction

with overcrowding resulted in soil erosion and Easter Island is located in the eastern Polynesia,

depletion, food shortages, and finally the collapse of

south-western Pacific Ocean and is known for its

society. The history of Easter Island shows that the

famous and imposing stone statues, the moai (Fig. 1).

sustainability of our civilization depends on both the

Discovered by Polynesians, most likely from nearby

ability to provide energy, food and other goods to a

islands, about 700-1100 BC, this island has been

population that grows quickly, without compromising

pointed out as an example for the warning of the

the long-term resources [1].


The first principle of the Rio de Janeiro Declaration on Environment and Development (1992) states that human beings are entitled to a healthy and productive life in harmony with nature, being at the centre of concerns for sustainable development [2]. The concept of sustainable development, defined as the






exploitation. Previous to the arrival of Europeans to Easter Island, which occurred in the Easter day of 1722, there was a drastic decline in the population of the island. The causes of this phenomenon have been attributed to the depletion of capacity of the local ecosystem. There is consensus that forests were subjected to extreme deforestation for agriculture, but also to aid the movement of gigantic rocks used in the construction of the moai. Recent investigations

ability to meet the needs of the present generation without compromising the ability of future generations to meet their own needs, was introduced in the late 80s, following the consolidation of modern

Pharmaceutical Green Chemistry: Is Just Green Chemistry or Is Something Else More?


environment. Green chemistry in its mature form can be considered an established discipline since about 15 years [9]. Several key authors have contributed greatly to the development of the interdisciplinary of green chemistry, such as P. Anastas and J. Warner (coined the term green chemistry and introduced its 12 principles) [3, 4, 10], B. Trost (atom economy concept) [8, 11], R. Sheldon (E-factor concept) [2, 12], J. Clark (“ideal synthesis” concept) [5, 13], among many others. The literature of green chemistry has undergone a dramatic increase in the last decade. These reports mainly concern more environment-friendly synthetic methods, based on better catalytic systems, less Fig. 1 Moai at Rano Raraku, Easter Island. (Author: Aurbina, re-used with permission from Wikimedia Commons at u.jpg).

harmful solvents and, more rarely, “alternative”

environmentalism, emerged in the ’60s/’70s. Among the most important objectives for sustainable development is the ability to reduce the harmful effects of chemicals that are generated by the human activities. Chemistry is the science of matter and its components, the chemical elements. Chemistry focuses on the study of atoms, in interactions between atoms and particularly in the properties of chemical reactions. It is through chemical reactions that matter transforms herself, generating chemical products or

suitable for the generation of libraries of compounds

causing the degradation of others. It is widely recognized that chemical sciences contribute decisively to the welfare of humanity, allowing thousands of products that are available to satisfy the needs of mankind. Therefore, chemistry plays an important role to ensure that the next generation of

The economic and social value of pharmaceuticals

physical techniques [9]. Some of these reports have been made in the field of pharmaceutical chemistry, such as in the development of chemical processes for biological evaluation and in the improvement of reaction conditions for the synthesis of compounds of pharmaceutical interest [14, 15] Pharmaceutical compounds range from structurally simple molecules to molecules that have a remarkable complexity that result from multistep synthetic routes, and have a high number of carbon atoms and several chiral centers. Therefore, the application of green chemistry to pharmaceutical chemistry brings a larger challenge. for mankind is well-known. However, in most cases, the chemistry involved in their industrial production is far from being green. The physical and chemical properties of these compounds as well as their pharmacodynamic and pharmacokinetic properties are

chemicals, materials and energy is more sustainable than the current generation. One of the most attractive concepts in chemistry for sustainability is Green Chemistry [3-8].

in most cases incompatible with straightforward

Green chemistry is a multi-faceted discipline that

Tucker [14] and contextualizes the usefulness of green

has been created as a contribution of chemistry to

chemistry principles in the persecution of the final

sustainable development, avoiding damage to the

goal of pharmaceutical chemists, which is deliver





Therefore, the new concept of pharmaceutical green chemistry have been introduced a few years ago by


Pharmaceutical Green Chemistry: Is Just Green Chemistry or Is Something Else More?

pharmaceutical active compounds suitable for the production of medicinal products that help in the treatment of diseases.

2. The Genesis of Green Chemistry The basic ideas of Green Chemistry were the result of a long progression by industrial process chemists and chemical engineers in order to make less harmful chemicals to the environment, to deal more effectively with the waste and to minimize waste generation [4, 16]. A decisive driven force for this new attitude from industry was the environmental legislation, which has become more stringent since the 80s [2]. Chemical products and processes, intrinsically generators of industrial waste and pollution, evolved towards more environmentally acceptable alternatives of chemical production. Technologies that could contribute to improve energetic efficiency, avoid the use of reagents and hazardous and/or toxic solvents and reduce or preferably eliminate the generation of hazardous and/or toxic waste were encouraged. Stress factors along the supply chain of chemical products, such as the increasing cost of raw materials and energy and the greater awareness about health problems associated with the handling of reagents, solvents, intermediates and final products become truly decisive in choices made in the implementation of new chemical processes. Chemical processes start to be analyzed on all prospects of the lowest environmental impact. This new paradigm has been designed by The Environmental Protection Agency (EPA) as Green or Sustainable chemistry [17]. The approach of academic research to the objectives of industrial chemistry, allowed the “final jump” to build the theoretical body of Green Chemistry, with the merger of several parent concepts and industrial activities (Table 1). The traditional concept of efficiency of a chemical process focuses exclusively on chemical yield [18]. The analysis of a chemical reaction from this point of view considers only the quantity of product obtained after purification and isolation. Motivated by

Table 1 Concepts and precursor activities of green chemistry (adapted from the literature [16]). Origin in the industrial chemistry/chemical industry -Prevention of pollution -Minimising the generation of waste and chemical waste -Safer chemical processes -Safer industrial processes -Respect for human health, safety and environment -Environmental concern in the design of chemical products and processes -Industrial Ecology Origin in the synthetic chemistry/academic institutions -Atom economy -Environmental Factor (E-Factor)

the response of the chemical industry in the quest for sustainability, many synthetic chemists from the universities and research institutes began to reflect on the seriousness of the problem of waste [18]. This change of view on chemical reactions, resulted in the introduction of the concepts of atom economy [8, 11, 19] and environmental factor E (E-factor ) [2, 7, 12, 18], that not only incorporated theoretical foundations of chemistry, but also allow their use as measures or metrics of the environmental impact assessment of chemical processes. The atom economy, also known as atom use or atom efficiency, was introduced in 1991 by Barry Trost, a professor at Stanford University, USA [8, 11, 19]. The atom economy is calculated by dividing the molecular weight of the product by the sum of the molecular weight of all substances that were used and produced in the stoichiometric equation of the involved reaction(s). This parameter is especially useful when the quantities of waste of alternative processes are compared. The factor E is defined as the ratio of the mass of waste per unit of product (E-factor = total waste (kg)/product (kg)]. This measure was introduced by Roger Sheldon, professor at the University of Delft, Netherlands, and measures the actual amount of waste produced in the process of producing a chemical [2, 7, 12, 18]. The E-factor takes into account the chemical yield, and includes reagents, solvents, waste, all chemical process aids and, in principle, even the energy involved (quantified as amount of fuel,

Pharmaceutical Green Chemistry: Is Just Green Chemistry or Is Something Else More?

although this is often difficult to calculate). The extent of the waste problem in the production of chemicals is readily apparent from the observation of the typical E-factors for various segments of the chemical industry (Table 2). The concept of green chemistry, which some authors also designated as sustainable chemistry, emerged in the early 90s [18]. Indeed, these two concepts are overlapping: sustainability is the common objective and green chemistry is a means to achieve it. A convenient definition of green chemistry has been given in a recent review by Sheldon [2]. This author stated that green chemistry efficiently utilises (preferably renewable) raw materials, eliminates waste and avoids the use of toxic and/or hazardous reagents and solvents in the manufacture and application of chemical products [2]. In order to move towards sustainability, green chemistry has been focused on a series of reductions that lead to economic, environmental, and social improvements (Fig. 2).

3. The Principles of Green Chemistry The theoretical body of Green Chemistry is vast. It has been originated in the chemical industry, Table 2

Fig. 2

incorporates contributions from academic researchers and reflects the legislative and regulatory developments in chemical and environmental sector [4, 18]. With brilliant simplicity, Paul T. Anastas (Environmental Protection Agency, USA) and John C. Warner (University of Massachusetts, USA) condensed the concepts, objectives and guidelines of green chemistry in what is known as consensually by the 12 principles of green chemistry (Table 3) [3, 4, 10]. Conceptually, these principles are derived from a basic guiding principle, which results briefly in the design of environmentally benign products and processes (benign by design). The importance of the concepts of atom economy and E-factor for green chemistry is easily noticeable when we see that these concepts formed precisely the first (waste prevention) and second (atom economy) principles of Green Chemistry. Although some of the 12 principles of green chemistry appear to be little more than the application of common sense to chemical processes, the truth is that their combined implementation requires a tremendous effort in the design and development of products or chemical processes.

E-factors across the chemical industry (adapted from the literature [2]).

Industry sector Oil refining Bulk chemicals Fine chemicals Pharmaceuticals

Annual production (tonnes) 106 – 108 104 – 106 102 – 104 10 – 103


E-factor Ca. 0.1 50 25 – > 100

Waste produced (tonnes) 105 – 107 104 – 5 × 106 5 × 102 – 5 × 105 2.5 × 102 – 105

“Reducing”, the heart of green chemistry, and the costs of waste (adapted from the literature [5, 6]).

Pharmaceutical Green Chemistry: Is Just Green Chemistry or Is Something Else More?


Table 3

The 12 principles of green chemistry (adapted from the literature [3, 4, 10]).

1. Prevent waste: Design chemical synthesis to prevent waste, leaving no waste to treat or clean up. 2. Maximize atom economy: Design synthesis so that the final product contains the maximum proportion of the starting materials. There should be few, if any, wasted atoms. 3. Design less hazardous chemical synthesis: Design synthesis to use and generate substances with little or no toxicity to humans and the environment. 4. Design safer chemicals and products: Design chemical products to be fully effective, yet have little or no toxicity. 5. Use safer solvents and reaction conditions: Avoid using solvents, separation agents, or other auxiliary chemicals. If these chemicals are necessary, use innocuous chemicals. 6. Increase energy efficiency: Run chemical reactions at ambient temperature and pressure whenever possible. 7. Use renewable feedstocks: Use raw materials and feedstocks that are renewable (e.g. from agricultural products or waste of other processes) rather than depleting feedstocks. 8. Avoid chemical derivatives: Avoid using blocking or protecting groups or any temporary modifications if possible. Derivatives use additional reagents and generate waste. 9. Use catalysts, not stoichiometric reagents: Minimize waste by using catalytic reactions. Catalysts are used in small amounts and, if recyclable, can carry out a single reaction many times. They are preferable to stoichiometric reagents, which are used in excess. 10. Design chemicals and products to degrade after use: Design chemical products to break down to innocuous substances after use so that they do not accumulate in the environment. 11. Analyze in real time to prevent pollution: Include in-process real-time monitoring and control during synthesis to minimize or eliminate the formation of by-products. 12. Minimize the potential for accidents: Design chemicals and their forms (solid, liquid, or gas) to minimize the potential for chemical accidents including explosions, fires, and releases to the environment.

Despite the existence of the 12 principles of green chemistry, there is no clear and widely accepted definition of green synthesis. However, there is a general agreement that the approach of a green synthesis






implementation of various innovative strategies and clean technologies, preferably combined, including: Development of chemical reactions with higher atom economy (maximizing the use of reagents); Catalysis [20], including organocatalysis [21] and biocatalysis [22, 23]; Alternative reaction media for replacing organic solvents, such as water [24, 25], ionic liquids [26-28], fluorous






reactions [30]; New energetic efficient methods or technologies, such as the use of photochemistry [31], microwave irradiation [32, 33] or microreactor technology [34]; Alternative synthetic routes that avoid the use of toxic reagents or solvents and with a lower number of steps [35]. From the application of the 12 principles of green Chemistry, comes the concept of “ideal synthesis” (Fig. 3), introduced by James H. Clark (University of York, UK) [5, 6]. The principles of green chemistry

direct the industrial and laboratory synthetic chemist towards the ideal synthesis, focusing it on a matrix that combines factors of chemical, environmental and economic nature, with aspects related to the health and safety of individuals, populations and the environment.

4. Pharmaceutical Green Chemistry 4.1 The Concept: From Green Pharmaceutical Green Chemistry



Although most people associate oil refining and bulk chemicals production more than pharmaceutical manufacturing with dirty processes and waste, the true fact is that the amount of waste is higher in the latter by a factor of 102 – 103, as can be seen by comparison

Fig. 3 The “ideal synthesis” matrix (adapted from the literature [5, 6]).

Pharmaceutical Green Chemistry: Is Just Green Chemistry or Is Something Else More?

of the respective E factors (Table 2) [13]. One of the reasons that explains the E factor of pharmaceutical chemistry is the very high commercial value of pharmaceutical compounds [36], which contributes significantly for the establishment of many highly inefficient processes in drug synthesis [13]. Other reasons include the physical and chemical drug properties, their lack of stability under rough conditions and the need of high levels of purity of the final products to respect regulatory specifications. Therefore, it is well established that the synthesis of drugs and its intermediates generally requires high levels of chemo-, regio- and stereoselectivity. Accordingly, the reactions are often performed under relatively mild conditions, but using organic solvents, stoichiometric reagents, metal-based catalysts and involving purification and isolation procedures by means of aqueous work-ups and chromatographic separations [14]. The application of the twelve principles of green chemistry can deliver higher efficiency and reduced environmental impact during chemical synthesis. Although most of these principles apply directly to pharmaceutical chemistry, due to its particular specificities, some do not. As pointed out by Tucker, green chemistry as portrayed by the twelve principles acts as a guide but does not wholly apply to pharmaceutical green chemistry [14]. A definition of pharmaceutical green chemistry was given by this author as the quest for benign synthetic processes that reduce the environmental burden within the context of enabling the delivery of our current standard of living [14]. In this context, this means having rapidly and easily available drugs in the market, at a lower cost, with high standards of quality. At this point it might be useful to understand the distinction between pharmaceutical green chemistry and good process chemistry. In fact, according to Tucker these two concepts do not overlap and pharmaceutical green chemistry is the ideal that one strives for, and is the pursuit of this ideal that leads to


ever better process chemistry [14]. Running parallel to pharmaceutical green chemistry is the concept of clean/green technologies. Thus, in order to achieve truly green processes, it is vital that there is an integrated approach considering both chemistry and the technology components associated to it [37]. Obviously, pharmaceutical green chemistry starts during the drug discovery phase [15]. The application of the green chemistry principles continues with an increased focus upon synthetic route selection and optimization of the drug candidates at the drug discovery/process R&D interface [14]. In fact, the integration of the green chemistry paradigm in both the drug discovery phase and the chemical process development is very closely related to the new integrative vision that is seen in the pharmaceutical chemistry industry, creating opportunities to improve the interface between drug discovery/process R&D [38-49]. Federsel has pointed out the main reasons that explain it: increasing pressure to achieve shorter times-to-market, from candidate drug nomination to launch; demand of considerable quantities of the chosen drug candidates right from the start for biological and clinical studies as well as for the development of pharmaceutical formulations; higher structural complexity of the target compounds which implies greater cost [38, 40, 41, 49]. 4.2 Green Chemistry Principles that do no Apply to Pharmaceutical Green Chemistry During the drug discovery research, chemists use expedient routes to prepare compounds in the early stages of drug development. Quantities, as small as 10 mg, prepared in the laboratory, are usually enough for the initial in vitro screenings [50]. At this level, the synthetic strategies are rarely suited for commercial scale production. Even less suited for that purpose are also the methods used to produce chemical libraries for high-throughput screening techniques [51]. When a promising compound is identified, higher quantities


Pharmaceutical Green Chemistry: Is Just Green Chemistry or Is Something Else More?

become necessary. For full-scale manufacturing the optimal synthetic route is ideally used. This route considers all factors involved in the preparation of the drug substance and is generally the most cost-effective [50]. Thus, by involving process chemistry right from the beginning with the development of optimized and shorter alternative synthetic routes for lead molecules [51], better final products, at a lower cost, using more environmentally friendly synthetic approaches, supplied in a faster way and at a lower cost, will surely be achieved. In this context, pharmaceutical green chemistry builds on the implementation of benign synthetic procedures that reduce the environmental impact associated with pharmaceutical chemistry [15]. The pharmaceutical green chemistry concept not only integrates the principles of sustainability associated with green chemistry, which determines how its implementation shall be made, but also points the importance of maintaining the standard living of modern society. This means having medicinal products quickly and easily available in the market, at a lower cost and with high quality standards. From that, some of the 12 principles of green chemistry are not amenable to implementation in the pharmaceutical chemical synthesis [14]. The principle 4 of green chemistry (design safer chemicals and products) is not applicable to pharmaceutical chemistry. In fact, medicinal products are precisely characterized by their pharmacological activity. Although safety concerns about medicinal products are exhaustively studied in phase I, II and III clinical trials, is their pharmacodynamic action in the human body that justifies their use in the treatment of medical conditions. An example that illustrates well this situation is the case of cytotoxic antitumor drugs. These compounds are always highly toxic, but as their use represent an improving in quality of life and/or life expectancy, their industrial production is mandatory and necessary. Of course, in some cases, the toxicity of a drug candidate is so great that it excludes its

future use in clinical treatments. However, it should be pointed out that it is not the 4th principle of green chemistry that primarily excludes it, but instead their pharmacological profile that it is not suitable. Another principle of green chemistry that is not applicable to pharmaceutical chemistry is the 10th (design chemicals and products to degrade after use). The pharmacological activity of a drug is dependent on its molecular integrity, which requires an adequate chemical stability. Moreover, the drug degradation processes must be well-known. In fact, the metabolism of an API is extensively studied in in vitro assays and in phase I clinical trials. In this context, it is important to determine if there is metabolization by hepatic enzyme systems or others. The elimination routes of the API and its metabolites should also be precisely known. Currently, the impact of pharmaceutical residues in the environment is an active topic of research, linking aspects of analytical sciences with green chemistry [52]. The development of new drugs is still centred at their pharmacological activity, safety and efficacy in clinical practice. However, the fate of the drug in the environment starts to be now a matter of concern, especially with drugs used in veterinary medical products. For veterinary medicines, the application dossier already demands an environmental risk assessment report. The 7th principle (use of renewable raw materials) can not also always be applied. In most of the cases, feasible synthetic routes have been designed using readily available chemical building blocks, most of them, directly of indirectly, obtained from non-renewable sources. Overall, as the concept of pharmaceutical green chemistry is not overlapping with the original concept of green chemistry, even processes using “not-so-good” environmentally friendly reaction conditions could be considered appropriate, if these processes are markedly advantageous when compared to other classical or non-classical approaches (e.g. use

Pharmaceutical Green Chemistry: Is Just Green Chemistry or Is Something Else More?

of metal catalyst for a high yielding reaction, instead of a less efficient, but greener catalyst). By this assumption, the final goal of pharmaceutical green chemistry is conquest: feasible and efficient chemical processes, developed to reduce the environment impact of the chemical synthesis to allow that APIs can be industrially produced. 4.3 Pharmaceutical Green Chemistry: Examples from the Pharmaceutical Industry In the past few years, some important achievements have been made on the pursuit of good pharmaceutical green chemistry. Several academic groups have moved towards the incorporation of the green chemistry principles in the development of new processes applied to compounds of pharmaceutical interest. With great impact in pharmaceutical chemistry, the optimization of catalysts and reaction conditions for olefin metathesis, cycloaddition reactions, oxidations and stereoselective reductions, Friedel-Crafts alkylations and acylations, among many other examples, highlighted the advances registered in this field [53]. From the pharmaceutical industry field, the last decade was marked by several important advances in the assumption of the green pharmaceutical chemistry concept in the daily activities. Recent reports show the increasing awareness of the pharmaceutical companies by green chemistry goals. Among other examples, the use of solvents in their synthetic procedures has been discussed by GlaxoSmithKline (GSK) Pharmaceuticals’ scientists [54], the importance of green chemistry metrics for chemical process development in the pharmaceutical industry was reviewed by Constable et al. [55], and a remarkable textbook entitled Green Chemistry in the Pharmaceutical Industry has been edited by Dunn (Pfizer), Wells (AstraZeneca) and Williams (former director of Pfizer UK Chemical R & D) [15]. In 2005, the American Chemical Society Green Chemistry Institute® (ACS-GCI®) and global


pharmaceutical corporations developed the ACS-GCI® Pharmaceutical Roundtable to encourage innovation while catalyzing the integration of green chemistry and green engineering in the pharmaceutical industry [56]. The activities of the Roundtable reflect its member's shared belief that the pursuit of green chemistry and engineering is imperative for business and environmental sustainability. Therefore, it is their mission to catalyze the implementation of green chemistry and green engineering in the global pharmaceutical industry. Under the behalf of the ACS-GCI Pharmaceutical Roundtable high quality green chemistry tools have been developed, such as the solvent selection guide, the process mass intensity calculation tool and the convergent process mass intensity tool [56]. In addition, the ACS-GCI Pharmaceutical Roundtable is a frequent and influential publisher. For example, an excellent perspective paper has been published pointing out key green pharmaceutical chemistry research areas for future improvement [57]. In this paper, a survey has been made concerning the chemical reactions that are currently being performed in pharmaceutical industries but that better reagents would strongly be preferred as well as aspirational reactions for better green pharmaceutical chemistry [57]. Other notable papers include the perspective on the current state of environmentally sustainable practices in medicinal chemistry with the aim of more widely sharing best practices and highlighting some potential future developments in this field [58] and the series of reviews concerning green chemistry articles of interest to the pharmaceutical industry [59-62]. In 1996, by initiative of the U.S. government, The Presidential Green Chemistry Challenge [17] was created with the aim of rewarding technological innovations that reduce the environmental impact of chemical processes, focused on three key areas: (1) synthetic pathways; (2) reaction conditions and (3) development of more environmentally acceptable chemicals. Since its creation, various chemical


Pharmaceutical Green Chemistry: Is Just Green Chemistry or Is Something Else More?

processes arising from the pharmaceutical chemical industry were awarded (Table 4).

dichloromethane and hexane (Fig. 4). As a result, the

One of the awarded greener synthetic pathways was

eliminate the formation of 92 kg of waste per Kg of

the new industrial process to prepare sertraline

E factor significantly reduced, thus managing to API produced [63, 64].

hydrochloride, an antidepressant marketed by Pfizer.

Another good example of how pharmaceutical

This new synthetic approach significantly reduced the

green chemistry can provide answers to the pressure

environmental impact of the production of this API.

imposed by the drug market arises from the

Among the improvements of this new process is the

production of generic medicines. When patents run

introduction of ethanol as the sole solvent, the

out, the cost of chemical processes finally takes on a

substitution of palladium catalyst (Pd/C) by a more

new meaning. At this point, the typical per kilo

efficient one (Pd/CaCO3), the elimination of the use of

market value of a given API substance drops

titanium tetrachloride and a 10 times reduction of the

substantially, and this economic factor creates a

total solvent used, allowing to eliminate the use of



chemistry [65].










Table 4 The Presidential Green Chemistry Challenge Awards winners from the pharmaceutical industry (data available from EPA website [17]). Greener synthetic pathways award winners Manufacturing of ibuprofen, an widely used anti-inflammatory drug (BASF, 1997). Development of biocatalysts for preparing LY300164, a new potential antiepileptic (Lilly, 1999). Efficient process for the production of Cytovene®, a potent antiviral agent (Roche, 2000). Application of green chemistry in the new industrial preparation process of sertraline (Zoloft® from Pfizer, 2002). Development of a green synthesis for the production of Taxol®, by cell fermentation and extraction (Bristol-Myers Squibb, 2004). New synthesis of aprepitant (Emend®), a potent antiemetic (Merck, 2005). New green synthesis of β-amino acids used in the production of sitagliptin (Januvia®), an oral anti-diabetic (Merck, 2006). An efficient biocatalytic process to manufacture simvastatin, an anti-dyslipidemic (Codexis, 2012). Greener reaction conditions award Enzymatic process involving a transaminase in the production of sitagliptin (Januvia®), an oral anti-diabetic (Merck and Codexis, 2010). Optimization of three bio-catalysts for the industrial production of an important chiral intermediate in the synthesis of atorvastatin (Lipitor®), an anti-dyslipidemic (Codexis, 2006).

Fig. 4

New green synthesis of sertraline (adapted from the literature [15]).

Pharmaceutical Green Chemistry: Is Just Green Chemistry or Is Something Else More?

5. Conclusions Nowadays, chemistry is moving towards the incorporation of the green chemistry principles into the development of new reactions and processes. This green chemistry paradigm has drawn the attention of pharmaceutical chemist’s community, and some important achievements have been made on under the auspice of the pharmaceutical green chemistry concept. In this perspective article, we traced a panoramic overview of how green chemistry principles can be adopted by the pharmaceutical chemistry, at the light of the stringent concerns of modern society. More than just apply green chemistry tools and concepts, pharmaceutical green chemistry must be focused on the final product, which is precisely a medical product intended to treat medical conditions. Examples coming from the academia or the pharmaceutical industry illustrate well how the developments of new chemical processes, oriented under the principles of green chemistry, can delivery efficient solution to afford new API or its intermediates. These examples show the way to accomplish the commitment of pharmaceutical green chemistry towards sustainability and medical breakthroughs with direct impact in human quality of life and life expectancy.

[7] [8] [9]

[10] [11]

[12] [13] [14] [15]

[16] [17] [18]

[19] [20] [21]

References [1] [2] [3]


[5] [6]

I.T. Horvath, P.T. Anastas, Innovations and green chemistry, Chem. Rev. 107 (2007) 2169-2173. R.A. Sheldon, E factors, green chemistry and catalysis: An odyssey, Chem. Commun. (2008) 3352-3365. P. Anastas, J.C. Warner, Principles of green chemistry, in: Green Chemistry: Theory and Practice, Oxford University Press, New York, USA, 2000, pp. 29-56. P.T. Anastas, M.M. Kirchhoff, Origins, current status, and future challenges of green chemistry, Acc. Chem. Res. 35 (2002) 686-694. J.H. Clark, Green chemistry: Challenges and opportunities, Green Chem. 1 (1999) 1-8. J.H. Clark, Green chemistry and environmentally friendly technologies, in: C.A.M. Afonso, J.G. Crespo (Eds.),




[25] [26] [27]


Green Separation Processes, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2005, pp. 3-31. R.A. Sheldon, Atom efficiency and catalysis in organic synthesis, Pure Appl. Chem. 72 (2000) 1233-1246. B.M. Trost, The atom economy: A search for synthetic efficiency, Science 254 (1991) 1471-1477. V. Dichiarante, D. Ravelli, A. Albini, Green chemistry: State of the art through an analysis of the literature, Green Chem. Lett. Rev. 3 (2010) 105-113. P. Anastas, N. Eghbali, Green chemistry: Principles and practice, Chem. Soc. Rev. 39 (2010) 301-312. B.M. Trost, Atom economy-A challenge for organic synthesis: Homogeneous catalysis leads the way, Angew. Chem. Int. Ed. 34 (1995) 259-281. R.A. Sheldon, Atom utilisation, E factors and the catalytic solution, C. R. Chim. 3 (2000) 541-551. J.H. Clark, Catalysis for green chemistry, Pure Appl. Chem. 73 (2001) 103-111. J.L. Tucker, Green chemistry, a pharmaceutical perspective, Org. Proc. Res. Dev. 10 (2006) 315-319. P.J. Dunn, A. Wells, M.T. Williams, Green chemistry in the pharmaceutical industry, WILEY-VCH Verlag GmbH & Co: 2010. A.A.S.C. Machado, Green Chemistry-From its birth to its teaching, Quim. Nova 34 (2011) 535-543. [Online], (accessed in the 20th September, 2013) R.A. Sheldon, Fundamentals of green chemistry: Efficiency in reaction design, Chem. Soc. Rev. 41 (2012) 1437-1451. B.M. Trost, On inventing reactions for atom economy, Acc. Chem. Res. 35 (2002) 695-705. W. Cabri, Catalysis: The pharmaceutical perspective, Catal. Today 140 (2009) 2-10. P.I. Dalko, L. Moisan, In the golden age of organocatalysis, Angew. Chem. Int. Ed. 43 (2004) 5138-5175. N.Q. Ran, L.S. Zhao, Z.M. Chen, J.H. Tao, Recent applications of biocatalysis in developing green chemistry for chemical synthesis at the industrial scale, Green Chem. 10 (2008) 361-372. J.M. Woodley, New opportunities for biocatalysis: Making pharmaceutical processes greener, Trends Biotechnol. 26 (2008) 321-327. H.C. Hailes, Reaction solvent selection: The potential of water as a solvent for organic transformations, Org. Proc. Res. Dev. 11 (2007) 114-120. C.J. Li, L. Chen, Organic chemistry in water, Chem. Soc. Rev. 35 (2006) 68-82. V.I. Parvulescu, C. Hardacre, Catalysis in ionic liquids, Chem. Rev. 107 (2007) 2615-2665. R. Sheldon, Catalytic reactions in ionic liquids, Chem.


Pharmaceutical Green Chemistry: Is Just Green Chemistry or Is Something Else More?

Commun. (2001) 2399-2407. [28] P. Wasserscheid, T. Welton, Ionic Liquids in Synthesis, Weinheim, Wiley-VCH Verlag GmbH & Co. KGaA, 2008, Vol. 1 and 2. [29] S.J. Tavener, J.H. Clark, Can fluorine chemistry be green chemistry?, J. Fluorine Chem. 123 (2003) 31-36. [30] G.W.V. Cave, C.L. Raston, J.L. Scott, Recent advances in solventless organic reactions: Towards benign synthesis with remarkable versatility, Chem. Commun. (2001) 2159-2169. [31] M. Fagnoni, D. Dondi, D. Ravelli, A. Albini, Photocatalysis for the formation of the C-C bond, Chem. Rev. 107 (2007) 2725-2756. [32] M. Nuchter, B. Ondruschka, W. Bonrath, A. Gum, Microwave assisted synthesis: A critical technology overview, Green Chem. 6 (2004) 128-141. [33] C.R. Strauss, R.S. Varma, Microwaves in green and sustainable chemistry, Topics Curr. Chem. 266 (2006) 199-231. [34] B.P. Mason, K.E. Price, J.L. Steinbacher, A.R. Bogdan, D.T. McQuade, Greener approaches to organic synthesis using microreactor technology, Chem. Rev. 107 (2007) 2300-2318. [35] S.J. Broadwater, S.L. Roth, K.E. Price, M. Kobaslija, D.T. McQuade, One-pot multi-step synthesis: A challenge spawning innovation, Org. Biomol. Chem. 3 (2005) 2899-2906. [36] K.C. Nicolaou, T. Montagnon, Molecules that changed the world, Weinheim, Wiley-VCH Verlag GmbH & Co. KGaA, 2008. [37] C. Jiménez-González, A. Curzons, D.J.C. Constable, M.R. Overcash, V.L. Cunningham, How do you select the “greenest” technology: Development of guidance for the pharmaceutical industry, Clean Prod. Processes 3 (2001) 35-42. [38] H.J. Federsel, Drug discoverers-you need us!, Drug Discovery Today 6 (2001) 397-398. [39] H.J. Federsel, Approaching chirality: Views from a pharmaceutical industry, perspective at the dawn of the 21st century, Chim. Oggi/Chem. Today 20 (2002) 57-62. [40] Federsel, H.J., Start small, think big-The art of process R&D, Nat. Rev. Drug Discovery 1 (2002) 1013-1013. [41] H.J. Federsel, Logistics of process R&D: Transforming laboratory methods to manufacturing scale, Nature Rev. Drug Discovery 2 (2003) 654-664. [42] H.J. Federsel, Searching for scalable processes: Addressing the challenges in times of increasing complexity, Curr. Opin. Drug Discovery Dev. 6 (2003) 838-847. [43] H.J. Federsel, Facing chirality in the 21st century: Approaching the challenges in the pharmaceutical industry, Chirality 15 (2003) S128-S142.

[44] H.J. Federsel, The role of Process R&D in drug discovery-Evolution of an interface, Chim. Oggi/Chem. Today 22 (2004) 9-12. [45] H.J. Federsel, Chemical process design in transition: Current trends in the pharmaceutical industry, PharmaChem. 4 (2005) 4-9. [46] H.J. Federsel, The integration of process R&D in drug discovery-Challenges and opportunities, Comb. Chem. High Throughput Screen. 9 (2006) 79-86. [47] H.J. Federsel, In search of sustainability: Process R&D in light of current pharmaceutical industry challenges, Drug Discovery Today 11 (2006) 966-974. [48] H.J. Federsel, Handing over the baton: Connecting medicinal chemistry with process R&D, Drug News & Perspectives 21 (2008) 193-199. [49] H.J. Federsel, Chemical process research and development in th 21st century: Challenges, strategies, and solutions from a pharmaceutical industry perspective, Acc. Chem. Res. 42 (2009) 671-680. [50] N. Anderson, Practical Process Research & Development, Academic Press, New York, 2000. [51] H.R. Marti, J.S. Siegel, Process chemistry in API development, Chimia 60 (2006) 516-517. [52] S.K. Khetan, T.J. Collins, Human pharmaceuticals in the aquatic environment: A challenge to green chemistry, Chem. Rev. 107 (2007) 2319-2364. [53] C.A. Busacca, D.R. Fandrick, J.J. Song, C.H. Senanayake, The growing impact of catalysis in the pharmaceutical industry, Adv. Synth. Catal. 353 (2011) 1825-1864. [54] D.J.C. Constable, C. Jimenez-Gonzalez, R.K. Henderson, Perspective on solvent use in the pharmaceutical industry, Org. Process Res. Dev. 11 (2007) 133-137. [55] D.J.C. Constable, A.D. Curzons, V.L. Cunningham, Metrics to “green” chemistry-which are the best?, Green Chem. 4 (2002) 521-527. [56] [Online], y-business/pharmaceutical.html. (accessed June 21th, 2014) [57] D.J.C. Constable, P.J. Dunn, J.D. Hayler, G.R. Humphrey, J.L. Leazer, R.J. Linderman, K. Lorenz, J. Manley, B.A. Pearlman, A. Wells, A. Zaks, T.Y. Zhang, Key green chemistry research areas-A perspective from pharmaceutical manufacturers, Green Chem. 9 (2007) 411-420. [58] M.C. Bryan, B. Dillon, L.G. Hamann, G.J. Hughes, M.E. Kopach, E.A. Peterson, M. Pourashraf, I. Raheem, P. Richardson, D. Richter, H.F. Sneddon, Sustainable practices in medicinal chemistry: Current state and future directions, J. Med. Chem. 56 (2013) 6007-6021. [59] I. Andrews, J. Cui, J. DaSilva, L. Dudin, P. Dunn, J. Hayler, et al., Green chemistry articles of interest to the

Pharmaceutical Green Chemistry: Is Just Green Chemistry or Is Something Else More? pharmaceutical industry, Org. Process Res. Dev. 14 (2010) 19-29. [60] I. Andrews, J. Cui, L. Dudin, P. Dunn, J. Hayler, B. Hinkley, et al., Green chemistry articles of interest to the pharmaceutical industry, Org. Process Res. Dev. 14 (2010) 770-780. [61] Andrews, I.; Dunn, P.; Hayler, J.; Hinkley, B.; Hughes, D.; Kaptein, B.; Lorenz, K.; Mathew, S.; Rammeloo, T.; Wang, L.; Wells, A.; White, T. D., Green Chemistry Articles of Interest to the Pharmaceutical Industry, Org. Process Res. Dev. 15 (2011) 22-30. [62] Amarnath, L.; Andrews, I.; Bandichhor, R.; Bhattacharya, A.; Dunn, P.; Hayler, J.; Hinkley, W.; Holub, N.; Hughes, D.; Humphreys, L.; Kaptein, B.; Krishnen, H.; Lorenz, K.; Mathew, S.; Nagaraju, G.; Rammeloo, T.; Richardson, P.; Wang, L.; Wells, A.; White, T., Green Chemistry Articles of Interest to the Pharmaceutical Industry, Org. Proc. Res. Dev. 16 (2012) 535-544.



G.J. Quallich, Development of the commercial process for Zoloft/Sertraline, Chirality 17 (2005) S120-S126. [64] G.P. Taber, D.M. Pfisterer, J.C. Colberg, A new and simplified process for preparing N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalen ylidene]methanamine and a telescoped process for the synthesis of (1S-cis)-4-(3,4-dichlorophenol)-1,2,3,4-tetrahydro-N-met hyl-1-naphthalenamine mandelate: Key intermediates in the synthesis of sertraline hydrochloride, Org. Proc. Res. Dev. 8 (2004) 385-388. [65] K. Gadamasetti, Process chemistry in the pharmaceutical industry: Challenges in an ever changing climate-an introduction, in: K. Gadamasetti, T. Braish (Eds.), Process Chemistry in the Pharmaceutical Industry, Challenges in an ever Changing Climate, CRC Press, London, 2008, Vol. 2, pp. 1-22.