Introduction
The production of active pharmaceutical ingredients (APIs) involves complex chemical transformations requiring precise control over reaction conditions and product purity. Traditionally, stoichiometric methods dominated API synthesis, often leading to substantial waste and inefficiencies. Catalysis has emerged as a transformative technology in this domain, enabling reactions with higher atom economy, selectivity, and scalability (1-3).
Catalytic reactions demand rigorous design, perfect control of the chemical space and a critical evaluation of all key parameters through the integration of clear performance metrics (4) and comprehensive economic analysis.
Factors such as turnover number, selectivity, yield, cost of goods, process safety, downstream purification requirements, catalyst recyclability, and environmental impact must be thoroughly assessed early in development. Without this structured framework, even catalysts with excellent laboratory performance may prove impractical or noncompetitive for industrial-scale API synthesis.
Catalysis comprehends a wide array of techniques, including heterogeneous and homogeneous organometallic catalysis, organocatalysis, biocatalysis, and transition-metal catalysis, see Figure 1. These approaches allow for the design of efficient synthetic pathways that minimize environmental impact and reduce costs. As pharmaceutical companies strive to meet regulatory, economic, and sustainability demands, catalysis has become indispensable in both discovery and manufacturing processes. A key component of production cost is energy consumption, a critical parameter that spans all catalytic technologies—enzymatic, and organometallic alike. While one of the advantages of catalysis is its potential to lower activation energy and enable reactions under milder conditions, this benefit is not automatic. The true energy profile of a catalytic process depends on reaction temperature and pressure, heating or cooling requirements, mixing intensity, and residence time. Biocatalytic processes, for example, often proceed at ambient conditions, dramatically reducing thermal input.
In contrast, some chemical catalytic reactions may require elevated temperatures or specialized energy sources (e.g., photoredox, or electron chemistry), increasing energy demand (5). Therefore, energy efficiency must be assessed holistically, considering not only reaction conditions but also utilities consumption throughout upstream and downstream operations. Integrating energy metrics into early process design is essential to evaluate both sustainability and operational feasibility at scale.
Homogeneous and heterogeneous organometallic catalysis
Transition-metal catalysts—such as complexes of palladium, ruthenium, and copper—are fundamental to numerous organic transformations, including cross-coupling reactions, hydrogenations, and oxidations. Key reactions like Suzuki–Miyaura, Heck, Heck–Cassar–Sonogashira, and Buchwald–Hartwig couplings are extensively employed in pharmaceutical synthesis to construct carbon–carbon and carbon–nitrogen bonds with high selectivity and efficiency under homogeneous conditions. Among the several example the use of the Heck-Cassar-Sonogashira for Erlotinib (5) or the use of the Suzuki-Myiaura reaction for Losartan (6). However, heterogeneous catalysis offers distinct advantages, such as higher turnover numbers (TONs) and simplified catalyst recovery and reuse. For example, in palladium-catalyzed processes, recovery rates under heterogeneous conditions often exceed 95%, whereas homogeneous systems typically achieve recoveries in the 80–95% range, posing challenges for cost-efficiency and sustainability. In addition, heterogeneous catalysis can be easily performed under flow conditions, an example of this combination is the synthesis of Donepezil (7). In this example the API synthesis was achieved with a sequential flow aldol condensation+heterogeneous hydrogenation catalysed by a dimethylpolysilane (DMPSi)/alumina-supported bimetallic Rh/Pt nanoparticle catalyst.
Biocatalysis
Biocatalysis utilizes enzymes to perform highly selective chemical transformations under mild conditions. Starting from hydrolases with time several classes of enzyme have been utilized at industrial level. The enzyme scope was expanded to oxidoreductases, kinases, transaminases etc. and solutions have been found for recover and recycle of cofactors. The development of more selective enzymes able to catalyze reactions with exceptional regio- chemo- and stereoselectivity under mild reaction conditions is the key of the biocatalysis success in the pharma industry.
A rational approach to enzyme optimization increasing the speed to design and select to optimal enzyme is now incredible faster than a few decades ago.
The main reasons are automation, easy access to plasmid and rational design.
In addition, the use of more sophisticated immobilizations technologies allowed to move from batch to continuous processes and has found widespread application in API synthesis from a few grams to tons.
In addition, performing biocatalytic transformation using supported enzyme allows to consistently increase the turn over number and decrease the cost impact of the enzyme, typical large-scale applications comprise the synthesis of antibiotics starting materials 6-aminopenicillanic acid (6-APA) and 6 amino cephalosporanic acid (7-ACA) and also final API like amoxicillin (8).
Another industrially significant example is the enzymatic synthesis of the antidiabetic drug Sitagliptin where Merck in collaboration with Codexis replaced a rhodium-catalyzed step with a transaminase enzyme, achieving higher yields, reduced solvent use, and improved environmental footprint (9). The enzymatic transformation was also performed in flow (10).
Organocatalysis
Organocatalysis has become an important tool in the pharmaceutical industry due to its operational simplicity, metal-free nature, and potential for environmentally benign processes.
A well-documented example is the synthesis of Nabumetone, a non-steroidal anti-inflammatory drug (NSAID), which utilizes an iminium ion-catalyzed aldol condensation developed in the 1980s (11).
This reaction exemplifies how organocatalysts can promote carbon–carbon bond formation under mild conditions, with good functional group tolerance and without the need for transition metals.
Despite these advantages, organocatalysis still faces several limitations that hinder its broader industrial application. One of the main challenges is the typically low turnover numbers (TONs) and turnover frequencies (TOFs) achieved with many organocatalysts, which can reduce process efficiency and increase production costs. Additionally, recovery and reuse of organocatalysts are often problematic due to their solubility. In the realm of asymmetric synthesis, the relatively limited variety of available organocatalysts makes it difficult to finely tune stereoselectivity and reactivity for different substrates, compared to the broader toolbox available in metal catalysis. However, when simple, cheap, largely available catalysts like L-proline can be used, organocatalysis becomes attractive like in the preparation of intermediates for Darunavir (12).
Green chemistry and sustainability
Catalysis aligns with the principles of green chemistry by improving atom economy, reducing waste, and minimizing energy consumption. Regulatory pressure and public demand for environmentally responsible manufacturing have encouraged the adoption of catalytic processes.
Catalytic methods often enable telescoped reactions, in which multiple steps are performed sequentially without isolating intermediates. High chemoselectivity—eliminating the need for protective groups—is essential for increasing the Ideality Factor (IF) of a synthesis (13). This approach reduces solvent use, waste generation, and energy consumption. Moreover, applying green chemistry principles—such as using non-toxic metals and renewable feedstocks—further enhances the sustainability profile of catalytic active pharmaceutical ingredient (API) production. Catalytic reactions also tend to scale up more easily than traditional organic reactions. In heterocyclic catalysis, the use of metal catalysts and immobilized enzymes supports process intensification, with plant miniaturization being a key factor for successful implementation (14).
The pharmaceutical industry has increasingly turned to catalysis to meet the goals set by the American Chemical Society’s Green Chemistry Institute Pharmaceutical Roundtable (ACS GCI PR). These include the replacement of hazardous reagents, solvent minimization, and implementation of catalytic over stoichiometric reagents wherever possible (15).
Importantly, integrating catalysis into green chemistry initiatives must also consider clear design metrics likeprocess mass intensity (PMI), Life Cycle Assesment (LCA), Ideality Factor (IF) and cost of goods (CoG). These allow chemists and engineers to quantify the environmental and economic impact of each catalytic step and optimize accordingly.
Challenges and future directions
Catalysis has become a cornerstone of modern API production, valued for its efficiency, selectivity, and potential for sustainability. However, realizing its full potential at an industrial scale requires careful evaluation of technical, economic, and environmental factors. A common misconception is that sustainable processes are inherently more expensive. In reality, when the entire process is assessed from a cost perspective—including raw materials, waste treatment, energy use, overhead and scalability—sustainable approaches can be both economically and environmentally advantageous. This cost analysis is a critical element of effective process design.
Economic and Environmental Constraints
A key challenge lies in the cost and regulatory burden associated with certain transition-metal catalysts, especially those involving rare or toxic elements like palladium, rhodium, or iridium. These must be removed to trace levels in the final API, necessitating additional purification steps.
The development of Earth-abundant metal catalysts—such as iron, nickel, or copper—has drawn significant scientific attention. These metals are inexpensive and widely available, offering an attractive alternative to precious metals. However, a simplistic focus on abundance or cost overlooks a critical issue: recyclability.
Unlike precious metals, which are typically recovered due to their high value, base metals are rarely recycled in practice—particularly when recovery processes are technically challenging or economically unjustifiable. Therefore, a holistic assessment of catalytic systems must consider not just reactivity and abundance but also the full lifecycle impact, including recovery, waste generation, and process complexity.
Technological Advancements Shaping the Future
To overcome current limitations and expand the impact of catalysis in pharmaceutical manufacturing, several promising avenues are being pursued:
• Holistic Development of Earth-Abundant Metal Catalysts. The development of catalysts based on Earth-abundant metals must take into account not only reactivity but also environmental impact and practical recyclability. Comparisons between organometallic reactions using rare metals versus abundant ones must be data-driven. For instance, comparing copper and palladium: copper is approximately 1,000 times cheaper than palladium and around 30 times less toxic. However, copper catalysis typically requires higher metal loadings. Due to its low cost, copper is often not recycled after use. In contrast, palladium, though expensive and less environmentally friendly, generally achieves higher turnover numbers (TON) and is therefore economically viable to recycle.
• Computational catalysis and artificial intelligence for predictive modeling of catalyst performance and reaction pathways.
• Integration of catalysis with flow chemistry and continuous processing, offering safer, scalable, and more consistent production.
• Advances in enzyme engineering and directed evolution, widening the substrate scope and operational robustness of biocatalysts.
These trends, supported by automation, data-driven process control, and sustainability metrics, will define the next generation of catalytic technologies in the API sector.
Conclusion
Catalysis has transformed the landscape of API production by enabling more efficient, selective, and sustainable chemical processes. From transition-metal catalysis to biocatalysis and asymmetric catalysis, these methods have unlocked new synthetic possibilities while reducing environmental impact. The combinations of catalysis technologies with flow chemistry can also increase process intensifications making industrial synthesis even more competitive.
However, in the modern pharmaceutical context, the success of catalytic processes depends not only on chemical performance but on a holistic design approach—guided by metrics such as process cost, atom economy, scalability, and environmental impact. By embedding these considerations into process development from the outset, catalysis can continue to drive innovation in the production of safer, more affordable, and environmentally responsible medicines.
Figure 1. Catalysis in API synthesis.
References and notes
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- https://acsgcipr.org/focus-areas/
