David J. C. Constable

Key green chemistry research areas—a perspective from pharmaceutical manufacturers

In 2005, the ACS Green Chemistry Institute (GCI) and the global pharmaceutical corporations developed the ACS GCI Pharmaceutical Roundtable to encourage the integration of green chemistry and green engineering into the pharmaceutical industry. The Roundtable has developed a list of key research areas. The purpose of this perspective is to summarise how that list was agreed, provide an assessment of the current state of the art in those areas and to highlight areas for future improvement.

Expanding GSK's solvent selection guide – embedding sustainability into solvent selection starting at medicinal chemistry

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.

Metrics to ‘green’ chemistry—which are the best?

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.

So you think your process is green, how do you know?—Using principles of sustainability to determine what is green–a corporate perspective

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.

Cradle-to-gate life cycle inventory and assessment of pharmaceutical compounds

Background, Goal and ScopeThe 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.MethodsLife 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.Results and DiscussionMajor 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.ConclusionsThis 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.

Method for selection of solvents for promotion of organic reactions

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.

A strategy to reduce the numbers of fish used in acute ecotoxicity testing of pharmaceuticals

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.

Green chemistry measures for process research and development

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.

Solvents in organic synthesis : Replacement and multi-step reaction systems

Abstract 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.

Systematic Selection of Green Solvents for Organic Reacting Systems

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.