Tools for Innovation in Chemistry
The ACS GCI Pharmaceutical Roundtable is dedicated to the implementation of green chemistry and engineering and member companies have collaboratively developed a variety of high quality tools and metrics to help scientists and engineers make better decisions about chemical selection and route and process design. All tools have been thoroughly vetted by Roundtable companies prior to their public release.
The impetus for tool development can be traced to the late 1990’s when early adopters in the Pharmaceutical industry began asking how green chemistry and engineering could be more broadly implemented in the industry. On the basis of early life cycle inventory/assessment of an active pharmaceutical ingredient, it became clear that chemical selection (i.e., solvents, reagents, etc.) played an enormous role in determining synthetic process cost and environmental, safety and health impacts across the life cycle. This insight led to the development of scientifically valid and industrially relevant bench level tools that could be used by scientists and engineers on a daily basis.
Process Mass Intensity (PMI) Metric
Process development chemists and engineers in Pharmaceutical companies are tasked with identifying efficient routes and processes to new chemical entities that become the active pharmaceutical ingredient in final drug products. The efficiency of any molecular synthesis is a combination of the strategy a chemist uses to assemble the different parts of the molecule (i.e., the route to the final target molecule through a series of isolated intermediates) and the subsequent effort to design and optimize the process (i.e., the combination of solvents, reagents, catalysts, process chemicals, etc. that enable bond-making and breaking).
Process mass intensity was proposed as a means of benchmarking green chemistry and engineering performance among member companies from the earliest days of Roundtable existence. The first PMI benchmarking exercise was held in 2008 and has been held on a regular basis ever since. PMI has helped the industry to focus attention on the main drivers of process inefficiency, cost, and environment, safety and health impact. Consequently, there has been a progression in tool development from a simple PMI calculator to a convergent PMI calculator, to one that allows a streamlined life cycle assessment, to others that allow standardized comparisons and the last which provides estimations of PMI based on the phase of drug development.
The contribution to green chemistry and engineering of this continuing initiative, and the latter two tools in particular, should not be underestimated. The ability to benchmark and predict process mass intensity of processes use to make complex organic molecules will enable scientists and engineers in academia and industry to develop better, more cost effective and more sustainable processes.
Process Mass Intensity Calculator
Decreasing the overall quantity of materials used to manufacture a final product is a significant challenge for pharmaceutical companies. Because of the large amount of solvent used in typical manufacturing processes, decreasing materials used saves companies money (less purchased and less energy used in workup and isolation). The Process Mass Intensity (PMI) metric was developed as a way to benchmark and quantify improvements towards greener manufacturing processes. The PMI Calculator enables you to quickly determine the PMI value by accounting for the raw material inputs on the basis of the bulk API output.
Convergent Process Mass Intensity Calculator
The original PMI calculator was enhanced to accommodate convergent synthesis in this second ACS GCI Pharmaceutical Roundtable PMI calculator. The Convergent PMI Calculator uses the same calculations, but allows multiple branches for single step or convergent synthesis.
Process Mass Intensity Prediction Calculator
The Process Mass Intensity (PMI) Prediction Calculator was created by the ACS GCI Pharmaceutical Roundtable member companies, with leadership from Bristol-Myers Squibb, to predict a range of probable process efficiencies of proposed synthetic routes at various phases of drug development. The tool uses historical PMI data from multiple pharmaceutical companies and predictive analytics (Monte Carlo simulations) to estimate the probable PMI ranges. The tool can be used to predict PMI prior to any laboratory evaluation of the route; i.e., as an in-silico modeling effort, or at any other stage of a molecule’s development to assess and compare potential route changes.
Green Chemistry Innovation Scorecard Calculator
This tool is a slightly different approach to accounting for PMI by focusing on waste. A joint effort by the IQ Consortium, ACS GCI Pharmaceutical Roundtable, and academic leaders, this Green Chemistry Innovation Scorecard web calculator illustrates how green chemistry and engineering innovation can reduce waste mass during bulk active pharmaceutical manufacture. The calculator uses a statistical analysis of 64 bulk active pharmaceutical manufacturing processes encompassing 703 steps across 12 companies to provide a relative process greenness score. This score may then be used as a means of making meaningful comparisons between different processes and their associated waste reductions.
Solvent Selection Tool
Given the importance of solvents to process mass intensity, solvent selection has been an area of intense interest to Pharma RT member companies. While there are a variety of solvent selection tools available, this is the first tool that has been developed by practicing pharmaceutical process development experts. This interactive tool enables you to select solvents based upon a variety of key solvent properties. Solvents which are close to each other in the principal components (PCA) map have similar properties, whereas distant solvents are significantly different. The tool enables you to download solvent property information such as physical properties, environmental, safety, and health data, etc. Originally developed by AstraZeneca, this tool was recreated for public access by the ACS GCI Pharmaceutical Roundtable.
Solvent Selection Guide
Choosing the right solvent is crucial to ensuring a more favorable sustainability profile of a batch chemical manufacturing process common to the pharmaceutical industry. In the pharmaceutical industry, more than 80% of materials used to manufacture bulk active pharmaceutical ingredients are solvents (including water). There are a number of solvent guides in use, including the Roundtables simple 2011 guide. However, the most current guide, recommended by the ACS GCI Pharmaceutical Roundtable, is the Chem21 Solvent Selection Guide.
View the Roundtable’s 2011 guide (archived)
Reagents are used to effect chemical transformations of all kinds, but generally, there are a limited number of transformations (e.g., oxidations, reductions, eliminations, etc.) that are routinely used by process chemists in developing a synthetic process. However, there are a variety of reagents for any given transformation, and not all reagents have equivalent performance when assessed across a range of green chemistry and engineering metrics. The reagent guides were developed initially within Pfizer to influence medicinal and process chemists to use greener reagents. Based on their success, additional guides were developed by member companies and shared across RT member companies. The reagent guides use Venn diagrams to provide an easy comparison of the scalability, utility, and greenness of reagents. Each reagent is extensively evaluated, examples of use are provided, and a broader greenness assessment with up-to-date references for each reagent is provided. These guides will improve your understanding of greener approaches to chemical transformations and also represent a great resource for educators.
MedChem Tips and Tricks
All parts of pharmaceutical development can be greened. A great example of this is the ACS GCI Pharmaceutical RoundTable Medicinal Chemistry Team’s approaches to greening medicinal chemistry. The ACS GCI PRT Medicinal Chemistry Team produced this quick guide covering purification, solvent selection, reagents, energy and resources.