Journal of Cleaner Production 7 (1999) 159166

Developing environmentally-sound processes in the chemical industry: a case study on pharmaceutical intermediates
Gerald Jo dicke
a b

a,*

Weidenhaupt b, Konrad Hungerbu , Oliver Zenklusen a, Andre hler

Safety and Environmental Technology Group, Chemical Engineering Department, Swiss Federal Institute of Technology, ETH-Zentrum, CH-8092 Zurich, Switzerland Centre de Ressources des Technologies pour lEnvironnement (CRTE), CRP Henri Tudor, b.p. 144, L-4002 Esch-sur-Alzette, Luxembourg Received 15 November 1998; accepted 30 November 1998

Abstract Life cycle assessment (LCA) is a widely accepted tool to quantitatively estimate environmental impacts of products or services. In this study, the LCA method has been applied to enantioselective reductions frequently used in synthetic chemistry. From these case studies three conclusions have been drawn. First, the environmental impacts as quantied by the method EcoIndicator 95 of biotechnology and metal catalysis are in the same order of magnitude. This is explained by the work-up procedures causing more environmental impact than the technology itself. Second, there are no a priori environmentally unacceptable catalytic methods. The environmental impact of a synthesis step depends rather on process parameters than on the technology employed. Finally, three parameters most important to an LCA of chemical reactions were identied: (1) the concentration of the reactants and, hence, the amount of solvent used, (2) all energy intensive steps such as distillations, and (3) the catalyst losses. 1999 Elsevier Science Ltd. All rights reserved.
Keywords: Life Cycle Assessment; Screening indicators; Chemical process assessment; Catalysis

1. Introduction Besides quality improvements and economical optimisations the chemical industry nowadays has to meet further criteria. Safety and environmental issues have become more important during the last decades and the chemical industry has undergone efforts in integrated process development [13]. Various methods and tools have been developed in order to specify the environmental progress achieved. The importance of life cycle assessment (LCA), representing one method for measuring environmental impacts, increases constantly [48]. Its importance is also emphasised by the international activities to standardise the method: in 1991 the SETAC proposed the four step procedure for a LCA with its Code of Practice [9]. The International Standard Organisation (ISO) is on the way to dening standards for the LCA [10]. Although plenty of publications under-

line the strength of LCA for the chemical industry [5,11 13] little work has been done to generalise the results and draw conclusions for simplied approaches [1417]. In this paper, the method of life cycle assessment will be used to quantify the environmental impact of four chemical processes. All four processes represent methods for the enantioselective reduction of ketoesters and therefore can be compared within narrow system boundaries. The main concern of this paper is to derive some generalised recommendations for the development of environmentally-sound processes. Those generalised recommendations line up with streamlining activities of SETAC-Europe [18,19] might overcome one of the major drawbacks of LCAs, namely the time intensive inventory analysis. Although aware of the evaluation methods shortcomings (e.g., in the assessment of toxicity effects, resource depletion, or the consideration of accidents), the authors do not intend to address this issue here.

* Corresponding author. Tel: 41-632-6885; Fax: 41-632-1189; E-mail: joedicke@tech.chem.ethz.ch

0959-6526/99/$ - see front matter 1999 Elsevier Science Ltd. All rights reserved. PII: S 0 9 5 9 - 6 5 2 6 ( 9 8 ) 0 0 0 7 5 - 4

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Table 1 Overview of the four case studies

2. Materials and methods Four case studies on enantioselective reduction were chosen for this investigation and are listed in Table 1. Two alternatives transform the -ketoester 2-oxy-4-phenylbutyric acid ethylester (OPBE) into the corresponding (R)-alcohol, while the other two reduction methods transform the -ketoester acetylacetic acid ethylester into the corresponding (S)-alcohol. These processes were chosen such that each transformation is represented by a bio-catalysed and a metal catalysed process. For the reduction of the -ketoester, either enzymes (D-LDH from Staphylococcus epidermis) [20] or a Pt/Al2O3 catalyst modied by chinchinodine [21,22] may be used. The -ketoester can be reduced using bakers yeast [23,24] or with a homogeneous catalyst Ru/BINAP [25]. All methods except the homogeneous Ru/BINAP process were developed by industry for a scale of approximately 100 kg per batch. Since the development of the Ru/BINAP process was still at the laboratory stage, a linear scale-up to a 100 kg batch process was applied for the assessment. The characteristics of each process are outlined in Table 2. All mass and
Table 2 Process conditions Case study Catalyst Reducing agent Solvent Temperature Pressure Yield (reduction) Enatioselectivity (ee) Reaction time Reactor type Literature
a

energy ows estimated for the life cycle inventory were derived from industrial operating instructions and were discussed with their developers in industry. The system boundary of this process LCA is visualised in Fig. 1. The inventory used includes all energy and material inputs as well as all emissions necessary during the operation of this system. Materials remaining within the system (e.g., buildings, batches) were assumed to be negligible compared to the amount of products produced with them. The substrate is not included in the system, since this paper focuses on the environmental impact of chemical reactions. The results of this case study will not be discussed relative to the impact of the substrate production but relative to each other. The mass and energy uxes of the industrial sewage treatment plant and the consecutive sludge incineration were estimated on the basis of a municipal sewage treatment plant [26]. Conservative transfer coefcients i.e., low elimination and degradation rates, were assumed in order to account for the uncertainties of the estimations (see Table 3). However, analysis of the case studies reveals that the transfer coefcients have only minor inuence on the results discussed later.

A1 D-LDH/NAD, regeneration via FDH Na-formate Water 30C Atmospheric 97% > 99% 1h continuous enzyme membrane-reactor [20]

A2 Pt 5%/Al2O3 dihydrochinchonidine Hydrogen Toluene 2030C 80 bar 97% > 82% 2h stirred autoclave [21,22,35]

B1 Yeast Sugar Water 30C Atmospheric 80% > 99% 48 h semibatch reactor [23,24]a

B2 [RuCl2[BINAP]]2*NEt3 Hydrogen Ethanol 80C 80 bar 98% > 97% 6h stirred autoclave [25]b

Operation instructions were provided by Prof. E. Hungerbu hler (IBB). Operation instructions were provided by Prof. E. Hungerbu hler and discussed with F. Spindler (Novartis Services).

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Fig. 1.

Upstream and downstream processes considered in the inventory: , materials, , processes.

Table 3 Assumptions made for mass ows attributable to the downstream and recycling processes Yield Stripping wastewater Solvent recycling Catalyst recycling Gas purication system Sewage treatment plant [26] 95% 95% 90% (Pt) 50% (Ru) 0% e.g. COD: 20% (into water) 50% (into air) 30% (into sludge) Comment Energy consumption depends upon the amount of polluted water Energy consumption is proportional to Hvap(Tb) Compared to providing new catalyst, the environmental impact due to the recycling process is negligible Worst case assumption Simplied model, conservative transfer coefcients estimated from physicalchemical properties

Steam (5 bar) is used for all heating purposes. UCPTE-mixed current is used as the electricity supply for all electrical equipment, i.e. stirrer and compressors. Not included in these case studies are measuring and control instruments, pumps for lling batches, cooling water and transportation of substances to and from the production site. The recycling loop refers to the metal catalysts only. Yeast and enzymes are assumed to be discharged to the sewage treatment plant in this case study. The effort for metal recycling has been excluded from the system under investigation for the following reasons: the metal concentration in the used catalyst is by orders of magnitude higher than in the ores, which allows the recycling process to be much more energy efcient. Furthermore, signicant amounts of sulphur dioxide are emitted when ores are roasted, which is not the case for metal recycling.

Direct solvent losses to the atmosphere are difcult to estimate but were assumed to be important for the results of the assessment. In this case study, direct solvent losses due to pressure release, solvent transfer, and solvent recycling were estimated in the range of 0.55% per operational step, based on physicalchemical properties of the solvents used: e.g., taking into account the different vapour pressures at operation temperature [27,28]. Table 3 summarises important assumptions for the mass ows within the system boundaries. Although all four case studies can be characterised as enantioselective reductions, they differ in their enantiomeric excess (ee). This difference is important for the environmental assessment and has to be accounted for since purication procedures might involve signicant efforts. However, for none of the case studies was an elaborate enantiomeric purication procedure available, partly because it was not necessary, partly because puri-

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cation is done several synthesis steps later. Therefore, two assumptions have to be made: rst, a best case scenario was assumed for each purication and no further efforts (such as extra solvents for purication) were taken into account. Second, the functional unit was dened as 1 kg of pure (100% ee, no impurities), desired enantiomer. Thus, only theoretically obtainable pure product is used here as reference for all case studies. The latter assumption takes into account that reduction methods with relatively low enantiomeric excess squander away energy and substrate for the generation of the undesired enantiomer and byproducts. Although with a best case scenario no extra efforts were added to the mass and energy inventory, product losses during a purication procedure were estimated by experts from industry and expressed as an overall yield: in the case of both metal catalysed reactions (A2 and B2), it was assumed that purication was necessary and that some product is lost. The homogeneous reduction (B2) (y 98%, ee 96% before purication) was assigned to an overall yield of 85% including losses due to purication. The heterogeneous reduction (A2) (y 97%, ee 82% before purication) was assigned to an overall yield of 70%, which is somewhat more pessimistic than in the case of B2. This more pessimistic assignment was chosen to account for the lower enantiomeric excess of A2, which might cause more problems during purication. In the case of both biochemical reduction methods (A1 and B1), having enantioselectivities higher than 99% it is assumed that no further purication will be needed for any application. Their overall yield is taken as 99% which means that 1.01 kg of product are equal to the functional unit. The inventory was evaluated using SimaPro 3.1S [29] and the evaluation method EcoIndicator 95 [30]. Further details of all four case studies can be found in [31].

3.2. M2: reduction Module 2 includes the production of all reagents necessary for the reduction, i.e., for the biocatalysed reduction nutrients (Na-formiate or sugar and nutrients), for the metal catalysed reduction solvents and for hydrogen. Volatile compounds, which are directly released to the environment when pressure is released from batches, are accounted for in this module. 3.3. M3: catalyst removal Four different procedures have to be considered for the separation of products from catalysts. The production of membranes for the separation of enzymes and product (A1) is neglected, since they can be reused for many production cycles. The heterogeneous platinum catalyst (A2) is removed by ltration and a 100% product recovery can be used in this case. The product in B1 is separated from the yeast by steam extraction. The process B2 uses toluene as solvent and the product is removed by distillation. For processes B1 and B2 a 5% product loss has to be considered due to product adsorption and thermal degradation. Wastewater sent to the sewage treatment plant in process B1 is considered here. 3.4. M4: extraction For both biocatalysed reductions (A1 and B1) an extraction from aqueous phase into organic solvents (A1: acetic acid ethylester, B1: diethyl ether) has to be considered. Only in exceptional cases will it be possible to continue the synthesis in aqueous media. Experts from industry estimated for this procedure approximately 5% product losses, which are released to the sewage treatment plant. The aqueous phase, which is saturated with organic solvents will be stripped before entering the sewage treatment plant. In module 4 only the solvent production will be considered. The solvent recycling is discussed separately in module 8. 3.5. M5: solvent drain off Finally, the product has to be removed from the solution. In all four case studies a distillation is used for this purpose. 3.6. M6: rectication A rectication is performed in case studies B1 and B2, which is taken into account in this module. 3.7. M7: enantiomeric purication As explained in the former section, the purication procedure has to be estimated as an overall yield, which is accounted for in this module.

3. Results and discussion The results of the life cycle assessment are shown in Fig. 2. The processes including the enantioselective reduction, work-up, waste treatment, and recycling, are described by modules M1 to M8, corresponding to the operating instructions. The introduction of these modules is straightforward to process chemists and supports a detailed interpretation of the results: 3.1. M1: catalyst This module comprises the production of catalysts and their modiers. For the sake of comparability, enzymes and yeast are considered as catalyst, although it is discharged after use. The metal losses during the recycling process are taken into account for platinum and ruthenium (see Section 2).

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Fig. 2. Modular presentation of LCA results for the case study enzymes (A1), Pt/mod* (A2), yeast (B1), and Ru/BINAP (B2). The curve shows the cumulative environmental scores according to the EcoIndicator 95 evaluation method.

3.8. M8: solvent recycling Organic solvents are considered to be recycled with an overall yield of 95%. The energy consumption is proportional to the solvents evaporation enthalpy (see Table 3). The recycled solvent is fed to the process again. The case study enzyme membrane reactor shows the negligible environmental impact of the enzyme production (A1M1) and the reducing agent formic acid ( 10% of total). The major contribution to the total environmental impact is due to the work-up; i.e., extraction into organic solvents (about 80%). The production of ethyl acetate contributes about 90% to the module M4, whereas 10% is due to direct solvent losses to the environment. The high environmental impact of solvent recycling can be explained by the energy intensive distillation and rectication (90% of A1M8). In the case study heterogeneous catalyst (A2), the catalyst losses contribute about 30% to the total environmental score although an overall platinum-recycling yield of 90% was assumed. The comparably low enantioselectivity of 82% causes another signicant contribution to the total environmental score of about 35%

(A2M7). Only small amounts of solvent are used in this process and hence modules M2, M3, M5 and 6, and M8 are less important. The enantioselective reduction using yeast (B1) shows a broad distribution of environmental scores to almost all modules. The production of yeast (B1M1) contributes about 10% to the total environmental score as large amounts of yeast are needed for optimal reaction conditions. The reduction step (B1M2) contributes about 15% which can be explained by the sugar fed to the yeast and the energy required to aerate the yeast. The solvent intensive extraction from the aqueous phase (20%, B1M4) and the solvent recycling (25%, B1M8) contribute most to the total environmental score. Again, this is owing to the production of the solvent itself and to the steam consumption during the recycling by distillation. An outstandingly low cumulated environmental impact, which is about one order of magnitude lower than each of the others, was obtained for the homogeneous Ru/BINAP process (B2). This remarkably good performance might be explained by two characteristics of this reaction: rst, the high substrate to catalyst ratio of 16 000 results in a negligible impact of ruthenium,

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although only 50% recycling of the catalyst was assumed. Second, the reduction is carried out at high concentration (60% w/w), which results in very low amounts of solvent required. Thus, modules M6 or M8 are almost negligible. The largest environmental impact within the whole homogeneous reduction process was assigned to the reduction step (35%, B2M2).

4. Conclusions Based on the four case studies, recommendations on different levels will be discussed. First, the discussion of biochemical transformations versus metal catalysis is considered. Second, the idea of unacceptables and criticals, as was introduced by Mak et al. [32], is compared to the results of this study. Finally, environmentally sensitive screening parameters are discussed, which can help as guidance for integrated process development. 4.1. Comparing technologies: biochemical transformations versus metal catalysis The discussion which technology is environmentally superior, the biocatalysed or the metal catalysed, cannot be decided in general. As shown for the cases A1 and A2, the environmental inuences of both technologies can be in the same order of magnitude. Depending on the process parameters and the assumptions made, either process type can perform better in the LCA. This is even more evident when the work-up modules are considered. The work-up procedures are usually the same for both technologies (distillation, rectication, and solvent recycling) and contribute 94% (A1), 53% (A2), 71% (B1), and 62% (B2) to the total environmental impact. In all cases, the results are more sensitive to the workup than to the technology chosen for the reduction module. For the heterogeneous reduction (A2), the environmental impact is almost equally inuenced by the production of the catalyst (recycling considered) and the comparably low enantioselectivity. 4.2. Comparing methods: are there unacceptable methods or chemicals? On the basis of these four case studies the following hypothesis is suggested for catalysed (i.e., nonstochiometric) reactions: there is neither a type of reaction nor a substrate which is a priori excluded from environmental competition with other reactions or chemicals. The difference between two substrate environmental impacts are usually almost negligible. This can be demonstrated as follows: given the reaction conditions of the best reaction (B2, homogeneous catalyst) but changing the solvent score from ethanol to perchlorethylene (which has relatively high environmen-

tal impact due to its ozone depletion potential), the environmental score of (B2) approximately doubles but still remains signicantly lower than all other reduction methods. The still superior result of the homogeneous reduction (B2) reveals that the environmental performance of one type of reaction evaluated with EcoIndicator 95 almost exclusively depends on the individual process conditions, and not on the specic substrates and solvents chosen. The environmental optimisation of a process at an early stage of its development shows parallels to that of an economical optimisation; at this early stage the performance of a chemical reaction can only be estimated and detailed process knowledge is necessary to predict the possible performance. It should be emphasised that the former hypothesis refers to environmental impact evaluations using the EcoIndicator 95 method or other LCA evaluations. Other concepts might disclose arguments that ban certain solvents or chemicals from industrial production. More sophisticated approaches for the environmental impact assessment of solvents can be found in [33,34]. Also worth considering is the fact that the environmental comparison of stochiometric reactions with catalysed reactions of average performance might have to be discussed differently. For stochiometric reactions, a minimal amount of reagent can be deduced from the stochiometric equation, independent of its process performance. This minimal amount of reagent might give an unmistakable judgement in favour of the catalysed reaction; e.g., in the case where stochiometric amounts of heavy metals are used and discharged or disposed of without recycling. The statements made in this section stress the importance of a case-by-case consideration, which is also important when process parameters like enantiomeric purity or by-products are regarded in more detail. The enantiomeric purity of the compound synthesised is one typical parameter to describe the quality of an enantioselective reaction; its importance depends on the desired purity and the specic behaviour of the substance considered. In the best case, the desired enantiomer precipitates spontaneously a few synthesis steps later and no further purication is required. In the worst case, there is no enantiomeric separation technique available and another process has to be developed. Therefore a generalised assessment of the products enantiomeric purity will always produce results in the range from zero to innite additional environmental impact due to purication and will cover all other uncertainties. The impact of enantiomeric purity to the environment can only be assessed in combination with all reactions following downstream. Similar conclusions may be applied to process specic by-products.

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4.3. Screening indicators for reaction conditions Although it is not possible to select environmentally benign synthesis pathways without precise process descriptions, it is possible to analyse the case studies for reaction conditions which are sensitive to the environmental rating. The most important parameters identied can then be used as screening indicators in order to pursue two goals. First, screening indicators are tools for decision making where no additional data are available (screening as simplication). The screening indicators derived from these studies may provide guidelines for process developers who consider environmental optimisations besides other criteria. Second, screening indicators may be used where time resources do not allow a detailed analysis of the situation (screening as acceleration). Carrying out a detailed LCA is time consuming and the authors are conviced that, today, it is unrealistic to establish the LCA method as a decision support tool for general use in the chemical industry. Screening indicators might be used to decide under time pressure which of a series of competing catalysed processes is more environmentally sound. Based on the four processes investigated here, the following reaction parameters were identied as being responsible for the environmental performance of a process: The concentration at which a process is carried out is crucial to its environmental impact, since solvent losses and solvent recycling have a high impact on the assessment. This is especially the case if halogenated solvents are used. It is necessary to check every process for energy intensive steps consuming steam, pressure or electricity. Recovery rates of metal catalyst might inuence the environmental performance of the process considered. It is therefore important to predict the amount of catalyst used and its recycling yield. These three parameters cover 89% (A1), 93% (A2), 63% (B1), and 76% (B2) of the detailed life cycle assessment results. In the case of B1 only two thirds of the analysis are covered by the screening parameters. However, an experienced LCA analyst would certainly identify another source contributing 12% to the whole LCA results, namely, signicant amounts of sugar that have to be fed as reducing agent to the yeast.

work-up of chemical reactions. Work-up procedures can dominate the entire process assessment due to the use of organic solvents for product extraction and the energy intensive solvent recycling. Therefore it was decided to investigate different work-up procedures omitting the use of organic solvents. In a case study, the product extraction using supercritical CO2 will be compared with a conventional separation by distillation.

Acknowledgements The authors wish to acknowledge P. Alean-Kirkpatrick (ETH Zurich), H.-U. Blaser (Novartis Services), R. Bretz (Ciba Speciality Chemicals), E. Hungerbu hler (IBB), H.-P. Jalett (Novartis Services), S. Mo ssner (ETH Zurich), M. Scheringer (ETH Zurich), E. Schmidt (Novartis), G. Sedelmeier (Novartis), F. Spindler (Novartis Services), and M. Studer (Novartis Services), for encouraging support and helpful discussions.

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