Tools for More Sustainable Chemistry

[ACSGCI]

On June 11, Helen Sneddon, Ph.D., Scientific Team Director in Medicinal Chemistry at GlaxoSmithKline, presented an overview of the ACS Green Chemistry Institute Pharmaceutical Roundtable tools during the 25^th Annual Green Chemistry & Engineering Conference. A summary of her presentation below provides a quick overview of these free public resources. You can also watch Dr. Sneddon’s complete 20-minute presentation at https://www.acsgcipr.org/tools-for-innovation-in-chemistry.  

The ACS GCI Pharmaceutical Roundtable (GCIPR) is the leading organization dedicated to catalyzing the integration of green chemistry and engineering in the pharmaceutical and allied industries. Established in 2005 by the ACS Green Chemistry Institute^®, the GCIPR has grown today to include 40 member companies motivated by the shared belief that green chemistry and engineering is imperative for business and environmental sustainability.

Early on, the GCIPR members recognized that chemical selection played an enormous role in determining the cost as well as the environmental, health and safety impact of a synthetic process. While other bulk chemical industries operate on larger scales, the number of steps required per Active Pharmaceutical Ingredient (API) and high purity requirements mean that the pharmaceutical industry produces a mind-boggling >10 billion kgs of waste per year with an annual disposal cost of >$20 billion.

To address this dual opportunity to reduce waste and cost, the GCIPR prioritized the development of tools for more sustainable chemical innovation. Today the Roundtable has developed a suite of tools that can be applied across various aspects of drug discovery and development. These tools have been identified, designed and thoroughly vetted by GCIPR member companies prior to public release.

Solvent Selection

In 2008, when GCIPR companies used Process Mass Intensity (PMI)—a measure of process efficiency—to benchmark processes, they found that on average organic solvents account for 56% of material used (water is another 32% of the total). Clearly, reducing the overall quantity of solvent waste through process intensification and solvent reuse was and is needed, but also necessary is looking at the nature of the waste and minimizing hazards present during synthesis.

Many pharmaceutical companies have created their own solvent guides over the years to address company priorities. Often developing these tools catalyzed further conversation and engagement around environmental considerations within the company. But how did the guides compare? When the GCIPR decided to amalgamate existing guides in 2011, they saw that despite varying approaches, the guides were mostly in agreement on the ranking of compounds, and discrepancies were minor.

Since then, the GCIPR Solvent Guide has evolved into the GCIPR Solvent Tool. Originally developed by AstraZeneca on proprietary software, the Solvent Tool was later donated to the Roundtable and rebuilt on publicly accessible software. Whereas previous guides were typically “traffic-light” style lists of rankings, the Solvent Selection Tool provides 2D representations of variables to facilitate selection based on molecular and physical properties, EH&S criteria, engineering, ICH guidelines, etc. There are 272 solvents in the tool’s data set and the free, publicly available tool is fully interactive with downloadable data. In addition to using filters to select solvents, you can select a group of solvents close to the solvent of interest in the plot. This gives you a selection of solvents with similar physical and chemical properties—something that might be useful if you are looking for a greener drop-in replacement, for example.

Acids and Bases Selection

Since the Solvent Selection Tool has proven to be so popular, a similar approach has been taken to develop an Acid-Base Selection Tool. While this tool is currently under GCIPR member review, it will be released to the public once it is vetted.  Currently, there are 101 acids and bases included in this tool, but more are planned to be added in future iterations.

The tool allows acids and bases to be filtered by selecting variables including functional groups, physical properties, EH&S criteria, GRAS (Generally Recognized as Safe), and a color-coded greenness ranking. Data points display 2D plots where acids and bases are arrayed based on their pKa in water vs. acetonitrile.  

Reagent Guides

Another valuable tool the Roundtable has put together is the extensive Reagent Guides—which currently include over 150 reagents across 19 of the most used transformations in the industry. Compiled through the collective expertise of the Roundtable members and extensive literature reviews conducted by Andy Wells (Charnwood Technical Consulting), these guides assess:

• The scope of the reagents – can they work in good yield across a wide variety of “drug-like” molecules?
• The scalability of the chemistry – can it be applied in both research and manufacturing?
• How green and sustainable is the chemistry – safety, atom economy, etc.

For each guide, a clickable Venn diagram helps visualize how reagents compare across the variables—wide utility, scalability and greenness. Importantly, the guides provide easy access to the chemical literature with links to reaction mechanisms, scale-up examples and green considerations.

Biocatalysis Guide

The Biocatalysis Guide serves as a quick reference for chemists who have had limited exposure to biocatalysis. It shows the most used biocatalysis transformations so that they can be factored into retrosynthetic analyses. For ease of use, the Biocatalysis Guide is a 2-page PDF print out and unlike the Reagent Guides, it does not include literature references. Fifteen transformations are covered. The substrate scope is scored red if the enzymes are substrate specific and green if broad in scope. The cofactors are scored red if the transformation requires multiple enzymes or is rarely used, yellow if it is commonly used or doesn’t require a second enzyme, or green if no cofactor or additional enzyme is required.

Analytical Method Greenness Score (AMGS Calculator)

Over the past decade improvements in high-pressure liquid chromatography—from HPLC to UHPLC—and supercritical fluid chromatography—from SFC to UHPSFC—have led to faster and more efficient separations. However, at present, many of these improvements have yet to be implemented. To encourage analysts to develop greener methods, this calculator provides a simple metric to enable a comparison of separation methods used in drug development. To benchmark and compare one method to another, the AMGS Calculator includes the solvent health, safety and environment impact, cumulative energy demand, instrument energy usage and method solvent waste. While the tool is not meant to be entirely quantitative, the lower the score generated, the greener the method is concluded to be.

PMI Calculators

To generate industry averages and benchmark progress, GCIPR companies have submitted (blinded) Process Mass Intensity (PMI) data over the years on late-stage and manufactured products. To calculate PMI, the Roundtable developed the PMI Calculator. The calculations are embedded within the excel sheet so that the chemist simply fills in the reagents, solvents and water used. The Roundtable also has a version that can process convergent sequences and is developing a third version that includes life cycle analysis. 

PMI Prediction Tool

While the PMI Calculator can be used retrospectively, the PMI Prediction Tool can be used to predict a range of probable process efficiencies of proposed synthetic routes and so can be used during the route selection process. As with the AMGS Calculator, the tool is not intended for precision calculations, but to enable relative rankings and ballpark figures. The tool uses historical PMI data from the GCIPR and predictions based on that baseline to establish probable PMI ranges. A breakdown of the calculations shows which step is likely to be most deleterious to the PMI.

Med Chem Tips and Tricks

Even earlier in the discovery pipeline, and addressing day-to-day behaviors in the laboratory, the GCIPR has condensed a wealth of knowledge into a list of tips and tricks for greener medicinal chemistry. Categorized by whether they relate to purification, solvents, reagents, energy or reactions, this is a great resource for those starting out in the lab or supervising undergraduates or interns.

We invite you to explore these tools and others not mentioned in this brief review. The GCIPR continues to update these tools on a regular basis and always welcomes your feedback to help improve the tools and supporting materials. Please contact acsgcipr@acs.org if you have any comments or questions.