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The pursuit of greener, more sustainable chemistry has increased over the past 20 years and there are now multiple journals, books, conferences and workshops produced every year. With all this acti...

Formulated products used in hydraulic fracturing are designed to address specific subsurface challenges during oil and gas well completion and are intended for the treatment of a myriad of issues i...

Summary Although the concepts underpinning green chemistry have evolved over the past 30 years, the practice of green chemistry must move beyond the environmental and human health-related roots of green chemistry towards a more systems-based, life cycle-informed, and interdisciplinary practice of chemistry. To make a transition from green to sustainable chemistry, one must learn to think at a systems level; otherwise green chemistry-inspired solutions are unlikely to be sustainable. This perspective provides a brief description of why the current situation needs to change and is followed by how life cycle thinking helps chemists avoid significant systems-level impacts. The transition from batch to continuous flow processing and novel approaches to isolation and purification provide a case for interdisciplinary collaboration. Finally, an example of end-of-useful-life considerations makes the case that systems and life cycle thinking from an interdisciplinary perspective needs to inform the design of new chemical entities and their associated processes., Graphical abstract, Highlights • Green and sustainable chemistry must include a systems and life cycle perspective • Green and sustainable chemistry requires extensive interdisciplinary collaboration • Catalysis, purification and isolation, and batch to flow processing are discussed, Chemistry; Organic chemistry; Green chemistry; Green engineering

To remain relevant, chemists need to be able to understand their work in terms of systems. Since systems thinking is a framework to understand and manage systems, the introduction of systems thinki...

The International Union of Pure & Applied Chemistry (IUPAC) launched a global project in 2017 to infuse systems thinking into chemistry education, motivated in part by the desire to help equip chem...

There is now over a 20-year history of green and sustainable chemistry efforts in the US, but for a majority of chemicals that have been synthesized, chemists and chemical engineers lack key information about what it takes to commercialize them, their toxicity to humans or the environment, their degradability (biological or otherwise), their ability to be recycled or reused, or their ability to be source renewably. While the depth, breadth, and variety of innovations in chemistry gives one hope that chemists and chemical engineers will make many significant advances in the next 20 years, there is still a need to incorporate systems and life cycle thinking into chemistry. This is especially true as one considers limitations in the supply of key elements chemists rely on very heavily. Recent advances in computational chemistry and machine learning show great promise for moving chemistry toward a more sustainable practice of chemistry.

This tutorial review presents an overview of the main metrics that have been used to test and compare the 'greenness' of processes and products, primarily in the pharmaceutical industry. The green metrics cover areas of resources, materials, processing, cleaning, life cycle assessment, renewability, amongst others. Application examples of these metrics are also presented to illustrate key points and concepts.

David J.C. Constable is the science director of the American Chemical Society's Green Chemistry Institute. In this role, he works to catalyze and enable the implementation of sustainable and green chemistry and engineering throughout the global chemistry enterprise.

The solvent selection methodology developed earlier by Gani et al. [Gani, R., Jimenez-Gonzalez, C., & Constable, D. J. C. (2005). Method for selection of solvents for promotion of organic reactions. Computers and Chemical Engineering , 29 , 1661–1676] has been extended to handle multi-step reaction systems as well as solvent substitution for specific reaction steps for existing processing systems. The problems were formulated based on the methodology guidelines, and solved using ICAS software tool [ICAS Documentation. (2003). Internal report . CAPEC, Department of Chemical Engineering, Technical University of Denmark]. Highly promising results were obtained, either in accordance with results previously published in the literature, or with industrial process data. This shows that the methodology has potential for application to complex reaction schemes as well as on the problems of solvent replacement.

A Green Technology Comparison framework incorporating a life cycle approach and sustainability metrics has been used to compare the performance, and the environment, health, safety, and life cycle impacts of two synthetic methods used to produce 7-aminocephalosporic acid (7-ACA). The routes under study were a chemical synthetic process and a two-enzyme catalyzed process, both starting from the potassium salt of cephalosporin C. Cradle-to-gate life cycle impact estimations were performed using the Fast Life Cycle Assessment of Synthetic Chemistry (FLASC™) tool and following modular gate-to-gate methodology. The results compare the synthetic efficiency, environment, health, safety, and life cycle metrics for a mature chemical process and a more recent but less developed enzymatic process for making 7-ACA. The chemical process has a higher yield, but a significantly lower reaction mass efficiency and half the mass productivity of the enzymatic process. The chemical process uses more hazardous materi...

The solvent selection methodology developed earlier by Gani et al. (Comp. Chem. Eng., 2005) has been extended to handle multi-step reaction systems. The solvent selection problem was formulated based on the methodology guidelines, and solved using ICAS software tool. A list with solvent candidates is generated so that it can be further investigated experimentally. Comments and clarifications from chemists have been incorporated into the problem formulations to clarify the role of the solvents in the chemistry and potential reactivity issues. Highly promising results were obtained, in accordance with Industrial process data.

Sustainable chemical engineering processes are best designed, implemented, and realized by taking a principled, sustainable, and green chemistry and engineering design approach from project inception. The application of these principles helps to frame in a manner that the scientist or engineer thinks about any given problem, process, or service they are working to implement. This chapter will lay out how chemistry and engineering principles must be integrated in the conceptualization and design in order for a more sustainable chemical engineering process to be developed.

The idea of preparing industrial and commercial products from bio-based and renewable materials is not a new one. Humans have relied on agriculture for food, clothing, and shelter throughout human history. In the 1930s, United States saw a resurgence of interest in producing a greater number of industrial and commercial products from agricultural sources, although this interest did not survive much past the end of the Second World War and the growth of the petrochemical industry. In recent years, there has been another resurgence of interest in obtaining chemical feedstocks from bio-based and renewable resources. This is largely a result of society being confronted by the inherent lack of renewability of petroleum and some of the large environmental impacts such as global climate change that are associated with petroleum, especially for transportation fuels. Turning these bio-based and renewable feedstocks into chemicals should be undertaken in a more sustainable way than what is currently being practiced in the chemical manufacturing enterprise. Sustainable and green chemistry are a way of thinking about and practicing chemistry and should be a hallmark of the transition to a bio-based, renewable and sustainable chemical manufacturing enterprise.

There is a clear need for simple methodology to deliver metrics that may be used to determine and benchmark the ‘greenness’ or relative sustainability of synthetic processes for Active Pharmaceutical Ingredients (APIs). Such methodology and metrics should facilitate more informed and sustainable business choices. This capability is particularly important at an early stage in R&D development activities when route and processes are being selected and detailed environmental data are not available. FLASC™ (Fast Life cycle Assessment of Synthetic Chemistry) is a web-based tool and methodology designed to meet these requirements. FLASC™ was developed from a detailed assessment of the cradle-to-gate life cycle environmental impacts associated with the manufacture of materials used in a typical pharmaceutical process. This paper describes the methodology used to develop FLASC™ and provides examples of the type of information and guidance FLASC™ provides. Both Hierarchical Cluster Analysis (HCA) and Principal Component Analysis (PCA) were used for the statistical analysis during the development of FLASC™. Benchmarking within the pharmaceutical industry and use of normalization for molecular complexity were also integrated to the tool. FLASC™ represents an important part of the overall efforts of GlaxoSmithKline (GSK) to incorporate and maintain sustainable business practices for manufacture of APIs used in its pharmaceutical products. This tool is not intended to assess waste from GSK operations nor solvent recovery and currently does not incorporate specific chemical-related health and safety data. However, these are already routinely assessed within GSK R&D at appropriate milestones and the use of FLASC™ is complementary to these evaluations.

Solvent use consistently accounts for between 80 and 90% of mass utilization in a typical pharmaceutical/fine chemicals (non-polymer) batch chemical operation. Moreover, within these operations, solvents play a dominant role in the overall toxicity profile of any given process; i.e. on a mass basis, solvents account for the largest proportion of chemicals of concern used in the process. However, for the typical synthetic organic chemist, solvents are just a medium in which a reaction takes place; the interest is in the reactivity and building of a molecule, not in the means by which this is carried out. So, in a typical retrosynthetic analysis, solvent and solvent-reactant interactions, separability, and particle engineering are generally not included. The best means in which this reaction can take place is also not considered; i.e., the reaction space, configuration, order of addition, heat/mass transfer, etc., is generally not considered. This publication presents a case for greater awareness of solvent...

A method to select appropriate green solvents for the promotion of a class of organic reactions has been developed. The method combines knowledge from industrial practice and physical insights with computer-aided property estimation tools for selection/design of solvents. In particular, it employs estimates of thermodynamic properties to generate a knowledge base of reaction, solvent and environment related properties that directly or indirectly influence the rate and/or conversion of a given reaction. Solvents are selected using a rules-based procedure where the estimated reaction-solvent properties and the solvent-environmental properties guide the decision making process. The current method is applicable only to organic reactions occurring in the liquid phase. Another gas or solid phase, which may or may not be at equilibrium with the reacting liquid phase, may also be present. The objective of this method is to produce, for a given reaction, a short list of chemicals that could be considered as potential solvents, to evaluate their performance in the reacting system, and, based on this, to rank them according to a scoring system. Several examples of application are given to illustrate the main features and steps of the method.

Solvents play an important role in the pharmaceutical, chemical and allied industries, with millions of tons used and disposed of each year. GlaxoSmithKline (GSK) previously reported on the development of a Solvent Selection Guide (SSG) that provides scientists with concise environment, health and safety (EHS) data and guidance for solvents. The Guide facilitates the inclusion of EHS considerations in early process development decisions.

The research presented here represents one part of GlaxoSmithKline’s (GSK) efforts to identify and improve the life cycle impact profile of pharmaceutical products. The main goal of this work was to identify and analyze the cradle-to-gate environmental impacts in the synthesis of a typical Active Pharmaceutical Ingredient (API). A cradle-to-gate life cycle assessment of a commercial pharmaceutical product is presented as a case study. Life cycle inventory data were obtained using a modular gate-to-gate methodology developed in partnership with North Carolina State University (NCSU) while the impact assessment was performed utilizing GSK’s sustainability metrics methodology. Major contributors to the environmental footprint of a typical pharmaceutical product were identified. The results of this study indicate that solvent use accounts for a majority of the potential cradle-to-gate impacts associated with the manufacture of the commercial pharmaceutical product under study. If spent solvent is incinerated instead of recovered the life-cycle profile and impacts are considerably increased. This case study provided GSK with key insights into the life-cycle impacts of pharmaceutical products. It also helped to establish a well-documented approach to using life cycle within GSK and fostered the development of a practical methodology that is applicable to strategic decision making, internal business processes and other processes and tools.

There is growing interest in introducing environmental, health, and safety considerations during early stages of process development to achieve sustainable processes and products. GlaxoSmithKline (GSK) has previously described the concept of a Green Technology Guide (GTG) within the broader context of its programs to move the company towards more sustainable business practices. The concept for the Green Technology Guide is a series of case-scenario comparisons that provide scientists and engineers with comparative environmental and safety information on technologies for operations commonly found in the pharmaceutical industry.

A considerable amount has been written about the use of metrics to drive business, government and communities towards more sustainable practices. A number of metrics have also been proposed over the past 5–10 years to make chemists aware of the need to change the methods used for chemical syntheses and chemical processes. This paper explores several metrics commonly used by chemists and compares and contrasts these metrics with a new metric known as reaction mass efficiency. The paper also uses an economic analysis of four commercial pharmaceutical processes to understand the relationship between metrics and the most important cost drivers in these processes.

There is widespread interest in government and industry in green chemistry and green technology. For truly “green” processes to be developed, scientists must take a concurrent, integrated approach that considers chemistry and technology. While it is vital to understand those things traditionally considered in technology selection such as operational, quality, and cost differences, it is equally vital to understand the associated environmental and safety issues that are inherent to the chosen technology. This is a major challenge and there is a clear need for guidance in this area. This paper proposes the concept of a “Clean/Green Technology Guide” as an expert system that would provide scientists and engineers with comparative environmental and safety performance information on available technologies for commonly performed unit operations in the pharmaceutical industry. At this stage, the framework has been developed to demonstrate the concept, using a metric set based on the concepts of sustainable development. This framework is used to evaluate the alternatives on a case-scenario basis, and will compare traditional and emerging technologies. A life-cycle approach is also used in the evaluation of the alternatives. This approach is illustrated by comparing batch, mini-, and microreactors.

An approach to quantitatively and systematically evaluate synthetic organic reactions and processes is described. This sustainability-based approach allows chemists to clearly assess whether or not chemistries and chemical processes are ‘greener’. The results of this work indicate that close attention to effective use and reuse of solvents will result in the largest gains for reducing life cycle impacts in batch chemical operations.

High-performance liquid chromatography (HPLC) and capillary zone electrophoresis (CZE) were used in biodegradation kinetic studies. This paper describes a rapid penciclovir separation using CZE with detection limits comparable to HPLC. The ionic-strength mediated stacking technique was employed while good resolution was maintained. With a shorter analysis time, comparable detection limits and no organic solvent consumption, CZE is a better method for penciclovir biodegradation studies than conventional reversed-phase HPLC (RP-HPLC).

This chapter covers the typical metrics that can be used to evaluate the greenness of chemical synthesis. The discussion also illustrates the need to develop green metrics for chemical processes in a holistic fashion and from a systems point of view across a range of disciplines, where trade-offs are often encountered amongst the metrics. Keywords: chemical synthesis; greenness; green engineering metrics; green chemistry

This tutorial review presents an overview of the main metrics that have been used to test and compare the ‘greenness’ of processes and products, primarily in the pharmaceutical industry. The green metrics cover areas of resources, materials, processing, cleaning, life cycle assessment, renewability, amongst others. Application examples of these metrics are also presented to illustrate key points and concepts.

A set of metrics has been developed which enables a simple assessment to be made of batch processes in terms of waste, energy usage, and chemistry efficiency. It is intended to raise awareness of green chemistry by providing a tool to assist chemists in monitoring progress in the reduction of environmental impact as they design new routes and modify processes.

Monotherapy and combination therapy were compared using optimal doses of liposomal amphotericin B, micafungin, or caspofungin in Aspergillus fumigatus pulmonary and disseminated infections. Mice were challenged intravenously (2.8 × 10 4 to 5.7 × 10 4 conidia) or intranasally (5.8 × 10 7 conidia) with A. fumigatus . Drugs (5, 10, or 15 mg/kg of body weight) were given for 3 or 6 days as single, concomitant, or sequential therapy (i.e., days 1 to 3 and then days 4 to 6). Mice were monitored for survival, and tissues were assayed for fungal burden and drug concentrations. Treatments starting 24 h postchallenge significantly prolonged survival in disseminated aspergillosis ( P < 0.002), but only liposomal amphotericin B treatments or treatments beginning with liposomal amphotericin B increased survival to 100% in the pulmonary aspergillosis model. Fungi in kidneys and spleens (disseminated) and lungs (pulmonary) were significantly decreased ( P ≤ 0.04) by liposomal amphotericin B, liposomal amphotericin B plus echinocandin, or liposomal amphotericin B prior to echinocandin. In the disseminated infection, liposomal amphotericin B and micafungin (10 or 15 mg/kg) had similar kidney drug levels, while in the spleen, 5 and 15 mg/kg liposomal amphotericin B gave higher drug levels than micafungin ( P < 0.02). In the pulmonary infection, drug levels in lungs and spleen with 5-mg/kg dosing were significantly higher with liposomal amphotericin B than with caspofungin ( P ≤ 0.002). In summary, treatment of A. fumigatus infections with liposomal amphotericin B plus echinocandin or liposomal amphotericin B prior to echinocandin was as effective as liposomal amphotericin B alone, and a greater decrease in the fungal burden with liposomal amphotericin B supports using liposomal amphotericin B prior to echinocandin.

Objectives We hypothesized that effective prophylactic treatment of fungal infections would require adequate drug penetration and retention at potential infection sites. Using a mouse model, we examined liposomal amphotericin B (L-AmB) biodistribution, cell localization and retention in kidneys, lungs, liver and spleen to evaluate effective dosing regimens for prophylaxis of Candida glabrata and Candida albicans infections. Methods Following treatment of mice with cumulative doses of L-AmB (60-225 mg/kg), a bioassay was done to determine tissue drug concentrations 12 h to 6 weeks post-treatment. Immunohistochemical staining with anti-amphotericin B antibodies was used for cellular drug localization. Mice were treated prophylactically with 15-90 mg/kg L-AmB and challenged intravenously 1-7 days later with C. glabrata or they were given a total of 60 mg/kg as daily or intermittent dosing followed by intravenous challenge with C. albicans 3 or 6 weeks later. Results On the basis of microg/g tissue, the relative amount of drug was in the order spleen > liver > kidneys > lungs. Amphotericin B levels were maintained above the MIC for many fungi for 1 week in lungs and for as long as 6 weeks in kidneys and spleen. Drug localized in kidney tubular epithelial cells and in macrophages of liver and spleen. In prophylactic models, fungal burden was reduced by several 1000-fold or was undetectable within target tissues (kidneys, spleen). Conclusions These observations underscore the importance of including drug tissue levels to obtain a better understanding of L-AmB efficacy. The sustained concentrations of bioactive AmB in many tissues provide a further rationale for investigating L-AmB prophylactic regimens.

Publisher Summary This chapter discusses the Glaxo Smith Khne's (GSK) experience for technology assessment for a more sustainable enterprise. One aspect of GSK Environment, Health and Safety (EHS) vision for environmental sustainability is to champion the research and implementation of increasingly sustainable technologies and processes. While developing and implementing these programs, it became increasingly clear that the greatest short to medium term gains toward more sustainable practices would be realized at the interface of chemistry and technology. While GSK Corporate EHS had developed considerable understanding of fundamental pharmaceutical industry chemistry and chemical processing approaches to more sustainable practices, there was a lack of understanding about the materials and energy efficiency implications related to technology selection. As a result, a Green Technology Guide (GTG) is developed for technologies and unit operations of interest to the pharmaceutical industry. The Guide is developed as a module of the existing Web-based Green Chemistry Guide, and was designed to provide scientists and engineers with comparative assessments of unit operations from a sustainability perspective.

Paroxetine hydrochloride hemihydrate (the active ingredient in Paxil) is a pharmaceutical compound used for the treatment of depression, social anxiety disorder, obsessive compulsive disorder, panic disorder, and generalized anxiety disorder. Paroxetine (PA) is extensively metabolized in humans, with about 97% of the parent compound being excreted as metabolites through the urine and feces of patients. Therefore PA and metabolites have the potential to be discharged into wastewater treatment systems after therapeutic use. PA and its major human metabolite (PM) were investigated using studies designed to describe physical/chemical characteristics and determine their fate and effects in the aquatic environment. A significant portion of the PM entering a wastewater treatment plant would be expected to biodegrade given the higher activated sludge solids concentrations present in a typical wastewater treatment plant. The potential for direct photolysis of PM is also possible based on photolysis results for PA itself. These results provide strong support for expecting that PA and PM residuals will not persist in the aquatic environment after discharge from a wastewater treatment facility. This conclusion is also supported by the results of a USGS monitoring study, where no PM was detected in any of the samples at the 260 ng/L reporting limit. The results presented here also demonstrate the importance of understanding the human metabolism of a pharmaceutical so that the appropriate molecule(s) is used for fate and effects studies. In addition to the PA fate studies, PM was investigated using studies designed to determine potential environmental effects and a predicted no effect level (PNEC). The average measured activated sludge respiration inhibition value (EC50) for PM was 82 mg/L. The measured Microtox EC50 value was 33.0 mg/L, while the Daphnia magna EC50 value was 35.0 mg/L. The PNEC for PM was calculated to be 35.0 microg/L. Fate data were then used in a new watershed-based environmental risk assessment model, PhATE, to predict environmental concentrations (PECs). Comparison of the calculated PECs with the PNEC allows an assessment of potential environmental risk. Within the 1-99% of stream segments in the PhATE model, PEC values ranged from 0.003 to 100 ng/L. The risk assessment PEC/PNEC ratios ranged from approximately 3 x 10(-8) to approximately 3 x 10(-3), indicating a wide margin of safety, since a PEC/PNEC ratio

Solvents make a large contribution to the environmental impact of manufacturing processes of active pharmaceutical ingredients (API), as well as playing an important role in other chemical industries, with millions of tons used and disposed of each year. GlaxoSmithKline (GSK) has previously reported on the both the development of a GSK solvent selection guide and the incorporation of solvent life cycle inventory and assessment information. The GSK solvent selection guide has been further enhanced by: • Revising the assessments of factors that impact process safety, separating reactivity from fire and explosion rankings. • More than doubling the number of solvents in the guide, to a total of 110 from the initial 47. • Adding a customised solvent selection guide appropriate for medicinal chemistry and analytical laboratories. The new GSK solvent selection guide enables GSK scientists to objectively assess solvents and determine whether existing or new solvents brought to market as ‘greener’ alternatives truly represent a more sustainable choice or whether they are just addressing a single issue associated with sustainability.

The pharmaceutical industry gives high priority to animal welfare in the process of drug discovery and safety assessment. In the context of environmental assessments of active pharmaceutical ingredients (APIs), existing U.S. Food and Drug Administration and draft European regulations may require testing of APIs for acute ecotoxicity to algae, daphnids, and fish (base-set ecotoxicity data used to derive the predicted no-effect concentration [PNECwater] from the most sensitive of three species). Subject to regulatory approval, it is proposed that testing can be moved from fish median lethal concentration (LC50) testing (typically using > or = 42 fish/API) to acute threshold tests using fewer fish (typically 10 fish/API). To support this strategy, we have collated base-set ecotoxicity data from regulatory studies of 91 APIs (names coded for commercial reasons). For 73 of the 91 APIs, the algal median effect concentration (EC50) and daphnid EC50 values were lower than or equal to the fish LC50 data. Thus, for approximately 80% of these APIs, algal and daphnid acute EC50 data could have been used in the absence of fish LC50 data to derive PNECwater values. For the other 18 APIs, use of an acute threshold test with a step-down factor of 3.2 is predicted to give comparable PNECwater outcomes. Based on this preliminary scenario of 91 APIs, this approach is predicted to reduce the total number of fish used from 3,822 to 1,025 (approximately 73%). The present study, although preliminary, suggests that the current regulatory requirement for fish LC50 data regarding APIs should be succeeded by fish acute threshold (step-down) test data, thereby achieving significant animal welfare benefits with no loss of data for PNECwater estimates.