Toward a More Holistic Framework for Solvent Selection - Organic

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Towards a more holistic framework for solvent selection Louis J Diorazio, David R. J. Hose, and Neil K Adlington Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00015 • Publication Date (Web): 18 Feb 2016 Downloaded from http://pubs.acs.org on February 20, 2016

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Organic Process Research & Development

Towards a more holistic framework for solvent selection Louis J. Diorazio,* David R. J. Hose,* Neil K. Adlington Pharmaceutical Technology and Development, AstraZeneca, Silk Road Business Park, Charter Way, Macclesfield, SK10 2NA, United Kingdom

ACS Paragon Plus Environment

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TOC figure


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ABSTRACT

An interactive tool has been developed to facilitate solvent selection allowing consideration of chemical functionality, physical properties, regulatory concerns and safety / health / environment (SHE) impact. Appropriate solvents can be identified prior to screening experiments and less desirable solvents can be replaced in established processes. Once a shortlist has been identified, the data can define experimental programmes or else be exported to a molecular properties prediction tool to assess suitability through e.g. solubility and partitioning.

Keywords: solvent selection, green chemistry, predictive model


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Introduction The correct choice of solvent is crucial to the design of an efficient and effective chemical process. From the earliest training, chemists learn how solvent choice can affect reaction mechanisms, kinetics and stereo-, regio- and chemoselectivity patterns during synthesis steps. When tasked with developing their own process, the student soon learns however that it is not just synthetic steps that are affected by solvent choice. Molecular properties such as pKa, partitioning and azeotropic drying are all solvent-dependant and can significantly affect work-up and isolation. Despite this, it is all too easy for solvent considerations to be limited to dissolution of reaction components, operating temperature window and minimising solvent residues in products. The consequences of poor solvent selection run beyond the lab or plant, solvents are the single largest contribution to the environmental burden from a manufacture as a consequence of energy consumption and waste disposal. Analysis by the American Chemical Society Green Chemistry Institute Pharmaceutical Round Table (ACS GCIPR) suggests that typically >70% of the waste from pharma processing can be viewed as solvent related (ie solvent and water consumption).1 Thus the correct selection of solvents provides a major stimulus to improving the environmental burden of our processes. From this it is clear that solvents exhibit a sphere of influence spanning from the molecular level through to global, environmental concerns. Most companies recognise the benefits derived from increased environmental awareness. Corporate, social responsibility programmes emphasise activities to reduce consumption of natural resources. Within AstraZeneca, more than half of the sustainability targets on the corporate website have a significant contribution from drug substance activities.2 Of course, we should not be totally surprised at this altruism since sustainable processes are generally


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accompanied by significant cost benefits also. The simple act of increasing a chemical yield leads to the purchase of less raw materials, greater throughput in processing and reduced waste disposal – each of which delivers a cost saving in its own right. Over the last 10 years, a further driver to consider in solvent selection has been the growing legislative burden. Initiatives such as REACH in the EU already pose a challenge to commonly used solvents.3 At the time of writing, the Authorization list for REACH does not restrict likely pharma solvents.4 The Candidate list however contains many familiar solvents such as common polar aprotics (e.g. N-methylpyrrolidinone (NMP)), ethylene glycol-based ethers (e.g. 2methoxyethanol,) and various chlorinated solvents (e.g. 1,2-dichloroethane).5 Furthermore, the Restriction list already contains such familiar solvents as toluene, chloroform and cyclohexane.6 While inclusion on these lists does not necessarily preclude their use in processing, it may place additional burdens on justifying their use. Inclusion of the dipolar aprotics in particular is already recognized as a potential issue for pharma due to the limited replacements available at the present time.7 This reinforces the need to demonstrate broad solvent screening prior to use of such solvents; our scientists need to be open to the idea of using alternatives and this might include less common solvents.

Published Solvent Guides In response to the issues highlighted above, many companies have developed bespoke solvent selection guides to aid scientists. These have typically been based on environmental concerns such as the guide originally developed within AstraZeneca (Figure 1). The AstraZeneca guide categorized 46 solvents against 10 criteria covering safety, health and environmental (SHE) impacts with a 1-10 rating for each criterion. This was presented as a simple Microsoft Excel® spreadsheet accessible via the corporate intranet. One advantage of such a simple approach is


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that the display is also very amenable to display in the lab as a poster maintaining visibility but this is balanced by the potential for outdated copies being retained. The main disadvantage however is the sheer amount of information presented which becomes difficult to consult effectively.

Figure 1. Extract from original AstraZeneca solvent guide

AstraZeneca was not unique in this approach and Pfizer,8 GSK,9 and Sanofi10 have all published details of their corporate guides and the associated ways of working. Furthermore the American Chemical Society Green Chemistry Institute Pharmaceutical Round Table (ACS GCIPR) has developed a solvent guide based on approaches and data provided by AstraZeneca and Pfizer. This comprises a detailed guide with 5 criteria (safety, health, environment air/water/waste) scored from 1-10, this is available for free download from the ACS GCIPR website.11 Interestingly and with a mind on facilitating access and future practices, the ACS GCIPR tool is also available as an App for mobile users.12 An assessment of solvent selection guides has recently been published by the CHEM21 consortium.13 This covered guides from


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AstraZeneca, ACS GCIPR, GSK, Pfizer and Sanofi and reported good consistency in terms of overall desirability. While any consideration of environmental concerns is to be welcomed, a further problem with some of these guides is that they are primarily focused on SHE aspects. The main purpose of a solvent – generally supporting and facilitating the specific process – is barely considered at all. Other actions are therefore necessary to provide a holistic response to solvent selection since a shortlist based solely on environmental performance is likely to be too restrictive for effective process screening. In response to this, Sanofi incorporated links to additional tabulated physical data in their guide.10 This provides access to more information but still only presents one solvent at any time. There is no ability to readily compare solvents in a user-friendly sense. Industry groups have therefore recognized the need to integrate green tools into mainstream development but not yet managed to deliver a 21st century solution. Here we report our recent efforts in improving the tools available to our scientists to enhance their ability to identify effective solvents for their processes.

Changing solvent selection in AstraZeneca From our observations, pharma scientists can be quite conservative in their choice of solvents and often don’t stray far from familiar options such as ethyl acetate, toluene and tetrahydrofuran. Selection is often based on trial and error or the contents of the nearest solvent cupboard which is generally dependant on other work being conducted in the lab. Alternatively, literature precedent may recommend the preferred solvent for a transformation although this, in itself, is often the product of a highly restricted screen focusing solely on reactive chemistry. The problem with this approach is that it is not necessarily clear in which direction to progress if the


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original choice is inappropriate. If ethyl acetate does not support a process should we consider changing to a higher ester, a more polar ester, a more polar solvent class or head elsewhere and, if so, to where (Figure 2) ?

Figure 2. How to replace ethyl acetate ?

Rather than start from such a narrow focus and broaden the selection, a more rigorous approach would be to start from a wider set of solvents in the first instance and filter down. The decision process should focus on those solvent properties that fulfill all the needs of the specific application to identify a shortlist. In order to achieve this, any tool must consider SHE aspects alongside typical process requirements. This is the approach we encourage within AstraZeneca where we have sought to integrate green principles into general development activities. By doing so, sustainability is embedded at all stages of development and we avoid the idea of developing a process and subsequently making it green. To facilitate this, we sought to broaden the scope of the solvent tool from its original environmental focus. Before addressing how we might develop such a tool, we considered the impact of choosing a solvent in a process and what factors might be relevant for different applications. Any such tool should be able to deliver shortlists of diverse solvents for screening purposes and those offering similar performance for optimization applications. Similarly reactive processing might consider different properties to recrystallisation.


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In our studies we have sought to avoid the temptation to include prescriptive advice as much as possible. We anticipated two issues with including authoritative statements. Firstly, it focuses entirely on the solvent and takes no account of the processing context. A statement such as ‘Replace dichloromethane with 2-methyltetrahydrofuran’ seems reasonable but recognition needs to be made of e.g. density changes, greater reactivity towards strong acids and solute chirality. Similarly, negative statements such as ‘Do not use NMP’ do not encourage future advisory approaches, it may be that NMP provides the least impactful solution to a problem e.g. by reducing steps count in a sequence or dramatically increasing yield. Within AstraZeneca, we have also used the potential impact of REACH to encourage consideration of less common solvents. Often these are simply under-used in pharma / academia rather than scarce but, importantly, they may not be familiar to a scientist or in a local solvent cupboard. We have taken the view that a solvent simply provides a medium that supports and facilitates the underlying application.

Guiding principles for the Solvent Pool The selection of solvents to be included in the database was guided by a number of loose principles: Currently used and recognised process solvents Research solvents Newer ‘green’ solvents from sustainable sources Historically common solvents Available data Whilst we fully support and encourage the use of environmentally benign and sustainable solvents, we also recognise that many solvents offer unique solvation properties that are


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mechanistically vital for some classes of reaction. The dipolar aprotic solvents DMF, DMA and NMP are a case in point since there is no commonly accepted replacement some for these solvents. Homologues such as N-ethyl- or N-butyl-2-pyrrolidone (NEP / NBP) have been promoted as alternatives to NMP, although some might suggest that this was simply an attempt to use the lack of environmental and health data that was available at the time to keep ahead of legislation.14 Not all the solvents we have included are anticipated to be long term processing solvents. We have included solvents such as 1,1,1,3,3,3-hexafluoroisopropanol that are often helpful in probing mechanistic aspects. Similarly, many reactions from the older literature use solvents that are far from ideal by today’s standards but the reported chemical transformations may avoid much longer synthetic routes. We have therefore included solvents such as benzene, carbon tetrachloride and hexamethylphosphoric amide (HMPA), this is far from condoning their use but allows them to be placed into context alongside other solvents to facilitate their replacement. The scientist can then make informed decisions about which other solvents might be practical alternatives. Increasing regulation has led to several new solvents being promoted as green or sustainable. Many of these green solvents have interesting and potentially useful properties but are not yet commercialised to the same extent as common solvents leading to limited industrial application examples of use. We have still sought to include some of these solvents since it promotes them for use during the screening process and also should provide industry examples of their application. We have also included a number of other molecular liquids that are not generally considered to be solvents in the usual sense. This is for several reasons, the first of which is related to creation


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of a Principal Component Analysis (PCA) map. In order to create a robust and meaningful map across a variety of chemical classes we wanted each class to have sufficient representative examples to ensure that the underlying, conceptual properties were properly represented within the model. The second is to challenge preconceptions regarding what constitutes a solvent, and to spark creativity and innovation. For example, ethyl benzoate might not be anyone’s first choice as a potential solvent, yet no one would think twice about using ethyl acetate. Similarly, benzylamine is more often thought of as a reagent but could also act as a solvent and a base. Some recognized solvents have not been included in the database however. Among these are ammonia and supercritical fluids since they require specialist equipment for their use. We have also not included room temperature ionic liquids (RTILs). This is not in relation to any judgement on their applicability but is more from a practical perspective in relation to creating the tool. The potentially infinite combination of anionic and cationic species allows for an overwhelming number of compounds15 to be included in the database. Furthermore, any understanding of solvation properties and their effect upon the mechanistic aspects of reactions is yet to be worked out to the same degree of understanding for RTILs as for traditional molecular solvents. Hence, there is no systematic, physically-based property set to support their inclusion in a PCA map although future advances might render this feasible. Using these principles of what constitutes a solvent, our present list contains 272 entries. These are generally low molecular weight materials that are liquid within a reasonable operating window. We have applied limiting criteria of melting point

Toward a More Holistic Framework for Solvent Selection - Organic

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