Green-by-Design Small-Molecule API Synthesis

When synthetic organic chemistry transformations were first developed, chemists did not take into consideration their impact on the environment; the goal was to transform one substance into another. Use of large quantities of organic solvents, toxic and hazardous reagents combined with the need to often heat or cool reactions, however, adds up to a significant carbon footprint. As a result, when producing small-molecule pharmaceuticals, which involves many reactions performed on larger scale, the impact to the environment can be significant. The pharmaceutical industry has been aware of the need to improve sustainability of its operations across the board and has been taking action to improve its performance. With respect to small-molecule API synthesis, one solution has been to take a green-by design (or
greener-by-design, according to some) approach to establish more sustainable synthetic processes from the outset.

Small-molecule synthesis evolving

The field of organic chemistry, the basic science through which small-molecule pharmaceutical agents are prepared, is constantly evolving, contends Martin Eastgate, executive director of chemical process development for Bristol Myers Squibb (BMS). “More efficient, effective, and safer reactions (key elements to sustainability) are being discovered every day. In essence,” he concludes, “our ability to prepare small-molecule pharmaceuticals is consistently ‘getting greener’.”

Indeed, sustainability is becoming a cornerstone of drug development, according to Mahesh Bhalgat, chief operating officer at Syngene International. As a result, he observes that small-molecule API synthesis is evolving to meet the twin goals of producing life-saving medications while minimizing its ecological footprint, ultimately benefiting both patients and the planet. “We strongly believe that in a world with a rising need for innovative healthcare solutions and urgent environmental actions, the pharmaceutical sector is at a crossroads where it can combine scientific development with sustainable practices.”

Greener-by-design principles

Applying the basics of ‘greener-by-design’ principles to small-molecule pharmaceutical synthesis is fairly common across the major pharmaceutical companies, with organizations highlighting their work to explore more sustainable approaches to drug manufacturing, Eastgate says.

Merck, for instance, along with many collaborators is active in advocating for green and sustainable science across industry and academia. “We work to develop new technologies, such as novel enzymes and catalytic reactions, that have sustainability impacts across the field,” notes Kevin Maloney, executive director of process chemistry at Merck. He points to the ACS Green Chemistry Institute Pharmaceutical Roundtable (GCI PR), with more than 30 members, including Merck, dedicated to promoting the adoption of green chemistry and engineering in the pharmaceutical industry, as an example of an industry group taking real action in this area.

Each company takes its own approach to designing synthetic routes to small-molecule APIs, but increasingly there has been a cultural shift toward sustainability practices, according to Bhalgat. “One of the most widely applied approaches leverages green chemistry principles during process development, which involves the engineering of chemical products and processes to reduce or eliminate the use and generation of hazardous substances,” he says.

Twelve principles of green chemistry

The 12 principles of green chemistry (1) guide small-molecule API process developers to use sustainable and non-toxic reagents and have the shortest possible synthetic route, with the fewest operations and highest yields possible to afford the most efficient process with the least waste, summarizes Patrick Fier, process chemistry principal scientist with Merck. He highlights five key factors that are affected: personnel safety, efficiency, selectivity, waste minimization, and the use of renewable resources.

“The safety of the API synthesis process is paramount. The reactants, solvents, and process conditions should be chosen with safety in mind and steps should be taken to reduce the likelihood of accidents or unexpected reactions,” Fier states. In addition, the use of high-yielding reactions and minimization of by-products and the number of reaction steps should be prioritized. By definition, then, the selectivity of reactions is crucial in ensuring the desired product is obtained, which drives the use of catalysis and highly selective reagents. Furthermore, Fier notes that recycling and reuse of materials such as solvents, catalysts, and reactants should be considered, as should the use of biobased or biosourced feedstocks and green solvents.

Overall, the selection of a sustainable synthetic method stresses resource conservation, reduces environmental impact, and increases compliance with regulatory norms, according to Bhalgat. “These strategies promote responsible chemistry by encouraging a healthier ecology and safer working circumstances,” he says.

Balancing sustainability and practicality

Green-by-design API synthesis does not occur in a vacuum. “Optimization of the way drugs are prepared sits side-by-side with the robustness needed to manufacture a drug with the quality, consistency, and purity needed for commercialization,” Eastgate notes.

In addition, Eastgate observes that the development of a novel therapeutic is a high-failure-rate activity. “That context provides a lens through which we need to consider the timing of investment (and the level of investment) in optimizing a molecule’s synthesis,” he says. Drug-development timelines are also very long, meaning committing to a synthetic method must be made long before launch, and changing synthetic methods post-launch is very difficult. Different APIs may also have different volume demand (from a few kilograms a year to 100s of metric tons). “Focusing on the right projects at the right time with the right perspective is critical to managing a large portfolio of drug candidates,” he concludes.

The most challenging aspect of attaining green-by-design small molecule API synthesis is balancing sustainability and practicality, agrees Bhalgat. “The synthesis of many pharmacologically active compounds is fundamentally complicated, necessitating multiple steps utilizing a variety of chemicals, solvents, acids, and bases with harsh reaction conditions. Changing these synthetic routes to greener approaches can be time-consuming and costly, or sometimes not possible (for example, a sulfonation or a nitration reaction), or both,” he explains.

There are various ways to articulate the many factors important to consider when evaluating the sustainability of a manufacturing route to an API. BMS often refers to the ‘three Ps of sustainability’—people (safety), planet (environmental impact), and portfolio (robustness, quality, efficiency, etc.), according to Eastgate.

All of these elements are important, Eastgate suggests. “When we discuss ‘greener-by-design’, the mind often slips purely to environmental sustainability. However, safety is foundational. Robustness during manufacturing is critical. The ability to deliver high-quality drugs is vital to every patient. Acting with urgency to deliver life-saving molecules is an imperative. As we consider greener-by-design, we have to be very nuanced in our thinking and broad-minded when considering how to implement this concept; it is important to globally optimize and not locally optimize only one parameter,” he comments.

A green culture is a must

A company culture that is committed to increasing sustainability across the board is, in fact, another key ingredient to successfully pursuing a green-by-design approach to small-molecule API synthesis. “Maintaining a sustainability-focused culture is an important piece of the green-by-design puzzle and one we choose to embrace as an opportunity to build engagement in our organization,” Maloney states.

At Merck, periodic evaluations of process metrics are routine and requisite within the process development workflow, so the entire R&D organization is involved in this type of decision-making, Maloney outlines. Additionally, the company hosts a Green and Sustainable Science Symposium annually with external leaders in green chemistry and sustainability, as well as internal talks, posters, and awards that allow Merck’s teams to showcase their work and exchange ideas.

Not always a simple solution

In addition to cultural and contextual challenges, there are also technical hurdles that must be overcome when attempting to successfully achieve green-by-design small-molecule API synthesis routes. “Over the past several years, the overall complexity of molecules in drug discovery and development has been increasing with new modalities, ultimately necessitating the invention of new types of synthetic chemistry reactions and even reactors to streamline their synthesis,” Fier observes.

In addition, while science is constantly improving, many current synthetic methods still require environmentally challenging conditions (solvents, reagents etc.) or the use of raw material that may be mined or produced in unsustainable ways, according to Eastgate. “Consequently,” he states, “methods that avoid organic solvents, rare elements, etc., continue to be needed.”

Green reagent availability can, in fact, be a significant problem. “Creating a diverse and dependable set of green reagents is a continuously challenging task,” comments Bhalgat. “Further development of a green chemistry ecosystem is needed so that not only smaller companies, but larger manufacturers with strong marketing channels are offering greener materials,” he adds.

Merck’s approach to solving this problem is to build molecular complexity rapidly from simple commodity chemicals using novel enzymes and multi-enzyme cascades, according to Fier. “Such approaches can enable access to stereochemically complex molecules that would require many steps and protecting-group manipulations using traditional chemistry approaches,” he says. Fier also stresses that as the molecule development field evolves, there is a critical need to advance new reaction discovery.

Multiple strategies

With most small-molecule APIs, there are countless potential synthetic routes that can be used to produce them. Not all of these hundreds of potential pathways can be physically evaluated in the lab, according to Eastgate. He believes the best approach is to combine predictive, real-time quantitative and retrospective assessments (predictive, developmental, and life-cycle analyses).

“Simulated assessments are used to down-select to only a few options to be explored in the lab using quantitative, real-time assessments to ensure the optimum choices are made during development. Highly detailed retrospective assessments serve as a feedback loop for continuous learning,” Eastman explains. He adds that once a compound is placed on the market internationally, it is extremely difficult to tweak/adjust the way it is made, so predictive and developmental assessments need to be robust to ensure a sustainable design is achieved right the first time.

During route scouting, Merck leverages synthetic chemistry innovation, high-throughput experimentation, and the application of enabling technologies (biocatalysis, chemocatalysis, photocatalysis, flow chemistry, etc.) to identify the most direct route (least number of chemical steps while maximizing convergency and yield) from commodity chemicals to API, with particular focus on the 12 principles of green chemistry.

“Our focus is on developing the most robust and sustainable process. To do so, we leverage data-rich experimentation and mechanistic understanding to optimize the process to maximize yield, minimize hazardous waste, and reduce energy consumption while trying to incorporate relatively environmentally benign reagents, solvents, and raw materials. Consistent use of reliable metrics is critical in evaluating the decisions made based on these experiments, along with comparing the types of reagents, solvents, and building blocks used,” Fier says.

In fact, having reliable metrics as a fundamental aspect of designing a green process is necessary to achieve process sustainability, Maloney notes. It is equally important, he says, to foster a culture of using those metrics to set objectives and evaluate routes throughout development. “Without these tools, it can be difficult to objectively compare process alternatives or to align on what it means to have a green synthetic route when communicating with partners,” Maloney contends.

Some of the best approaches to selecting the greenest/most sustainable synthetic routes rely on the use of a range of metrics, agrees Bhalgat. The E-factor is the mass ratio of waste to desired product (2) and considers waste byproducts, leftover reactants, solvent losses, spent catalysts, and catalyst supports (3). Green solvent selection guides can be used to assess environmental impact, and life cycle assessment (LCA) provides information on the overall sustainability of the process, he adds.

“Collaboration among cross-functional groups (chemists, engineers, and sustainability experts) ensures a thorough examination of the process, which when overlaid with green chemistry principles and followed by an economic viability assessment, leads to selection of the greenest/most sustainable option,” Bhalgat comments. “This approach guarantees that the chosen strategy not only minimizes environmental impact but also corresponds with practical industrial needs,” he contends.

A few inhouse tools

Many pharmaceutical companies and contract development and manufacturing organizations (CDMOs) use not only tools developed by outside organizations, but proprietary solutions developed internally.

Merck, for instance, developed SMART-PMI, which leverages large data sets to provide predictive PMI values of target PMI values for any API based on the chemical structure, with the aim of setting aggressive targets to drive innovations in green chemistry. “The goal is to set the baseline for what a ‘good’ PMI is for a given molecule and provide ambitious targets. By utilizing this tool, chemists are challenged to invent new synthetic strategies that make the biggest impact to PMI,” Fier explains. In addition, Fier notes that as innovation in green chemistry leads to improved PMIs, these data can help drive more aggressive targets for the model.

The company also uses a Streamlined PMI-life cycle analysis tool to calculate these metrics for processes and evaluate them against alternate routes, digging deeper into the potential lifecycle impact of each synthetic step to highlight areas where additional development could yield substantial improvement.

BMS, meanwhile, has developed a number of tools internally that help assess the potential of various synthetic routes for APIs. Some have been published and released as apps in collaboration with the GCI PR, according to Eastgate, such as a tool for predicting the potential PMI of synthetic routes under consideration (the PMI Calculator) (4). “Our culture focuses on developing excellent internal tools, merging them with the best external tools, the expert opinions of our scientists, our prior internal knowledge as a team, and our industry’s institutional insight—all of which are vital. Sustainability of API manufacturing is not a single-point assessment; there is no one tool that we can use,” he emphasizes.

Opportunities for improvement

Continuous progress toward green-by-design small-molecule API synthesis provides ongoing potential for refinement. Greener synthesis processes, says Bhalgat, can be supplemented by more sustainable purification procedures, such as membrane separation or alternative crystallization methods. Techniques for minimizing the energy intensity of processes, such as microwave or ultrasonic-assisted reactions, could improve efficiency. The use of artificial intelligence and machine learning to identify alternative reagents and synthetic routes has significant potential as well. Wider use and review of metrics for green chemistry will also drive more clarity around management interest in green-by-design API synthesis.

Even though the field of organic synthesis is highly advanced, adds Maloney, researchers are always seeking new innovations and ways to develop sustainable methods for synthesizing APIs. Merck routinely seeks to identify major gaps in existing synthetic methodologies with respect to the need for more environmentally benign reaction conditions and streamlined routes.

Technology is constantly advancing, Eastgate agrees, and the industry should be seeking to bring innovations into pharmaceutical manufacturing as quickly as possible to improve sustainability. One area of particular opportunity for him is the combination of data science with organic chemistry, which he sees as creating significant opportunity for innovation. “We are on the cusp of a significant digital revolution within organic chemistry, with data analytics, modeling, and simulation based on large lakes of high-throughput reaction data from large screens significantly improving our ability to rapidly develop more efficient and sustainable synthetic routes,” he believes.

“The ultimate goal,” Maloney says, “is to have a ‘zero waste’ API manufacturing process. With this ambition in mind, the pharmaceutical industry must continue to invest in the development of new synthetic methodologies and enabling technologies that rapidly and efficiently build molecular complexity with simple and relatively environmentally benign reagents.”

The speed at which the pharmaceutical industry is moving toward sustainability must be increased, however, contends Bhalgat. “The ecosystem must evolve through a comprehensive exercise wherein scientific solutions are developed, evaluated, and implemented. Incentivization approaches must be brought in, such as priority review and rapid regulatory approvals for drugs developed using green chemistry technologies,” he observes.

CDMOs in particular, Bhalgat says, have the potential to make a significant difference in the pharmaceutical industry’s journey toward sustainability. “Outsourcing partners may expedite the adoption of greener processes, ethical practices, and environmentally friendly solutions through the integration of innovative technologies, collaborative alliances with multiple clients, and adherence to best industry practices,” he comments.

Ongoing investment and innovation

Pharmaceutical companies and CDMOs alike are investing in the development of sustainable methods for synthesizing APIs. Green-by-design approaches that focus on renewable raw materials, non-toxic and sustainable solvents, and efficient processes are gaining momentum, according to Maloney. Companies are also leveraging technologies like flow chemistry and biocatalysis to achieve sustainability by realizing greater process efficiencies and lowering environmental impacts.

In fact, Eastgate believes there is great opportunity in the next 5–10 years to make significant strides in improving the sustainability of small-molecule manufacturing. “The coupling of improved synthetic methods with data analytics and predictive modeling/simulation will be critical going forward, as decision making is really at the root of improving sustainability,” he states.

“Having greater tools to explore the options through modeling/simulation to bring the greater longer-term consequences and perspective (What would the environmental impact be? Would this be robust? What risks will we face in developing this approach?) are key questions that we are getting closer to being able to understand … at the very stage when we are generating the ideas we want to try,” Eastgate adds.

Given these developments, Bhalgat believes that the trajectory of small-molecule API synthesis is moving decisively toward a more sustainable future and some significant shifts should be expected. “As environmental concerns grow, the pharmaceutical industry is embracing greener practices; however, this trend needs to intensify further. Innovation in green chemistry principles, catalysis, and alternative reaction methods will drive the development of processes that reduce waste, minimize energy consumption, and employ safer reagents. Continuous flow technology, biocatalysts, and AI-driven approaches will become more vital, enabling precise control, selectivity, and resource efficiency. A deeper understanding of the process impact on the products and impurity profiles will also be crucial to understanding the level of control needed on process parameters. Collaboration among researchers, industry, and regulatory bodies will foster the exchange of knowledge and best practices.

To fully implement green chemistry principles across the world, however, Maloney cautions that cultural shifts and ongoing investments in innovative technologies, education, and training will need to be undertaken.

References

1. Anastas, P. T. and Warner, J.C. Green Chemistry: Theory and Practice, Oxford University Press, New York (1998).
2. Manahan, S.E. The E-Factor in Green Chemistry. LibreTexts™ Chemistry
   (accessed Aug. 28, 2023).
3. ACS Green Chemistry Institute. Recap of the SELECT Criteria (accessed
   Aug. 28, 2023).
4. ACS Green Chemistry Institute. PMI Calculator.

About the author

Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology®.

Article details

Pharmaceutical Technology
Vol. 47, No. 10
October 2023
Pages: 18-23

Citation

When referring to this article, please cite it as Challener, C.A. Green-by-Design Small-Molecule API Synthesis. Pharmaceutical Technology 2023 47 (10).