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Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.
Advances in chemical synthesis are enabling greener, more cost-efficient processes for API manufacturing.
While most basic research occurs in academia, contributions from industry are also undeniably significant and impactful, according to Jeff Song, director of development at Boehringer Ingelheim (BI) Pharmaceuticals. Several pharmaceutical companies have established strong R&D organizations that routinely discover innovative and practical chemistries, and technology companies such as Johnson Matthey and Codexis also engage in original research to provide new chemistries for API synthesis.
In addition, both academia and industry are increasingly seeking opportunities for collaboration in precompetitive spaces, either through individual research agreements or multi-party consortia, according to Song. He notes that BI was one of the founders of the BI-Pfizer-AbbVie Consortium for Non-Precious Metal Catalysis, Flow Hydrogenation, and Computer Aided Synthetic Design. BI is also an industrial sponsor of the National Science Foundation’s Research Center, Center for Rational Catalyst Synthesis, and is intimately involved in its projects.
Two areas of technology have emerged in recent years as particularly important for API manufacturing: flow chemistry and catalysis. “Both can be applied to a broad scope of APIs. Catalysis provides shorter/more atom-economical, more cost-effective, and greener processes, while also providing novel reactivities that were not accessible before. Flow chemistry is another green technology that expands the horizon of the types of chemistry that can be used for making bulk APIs,” states Chris Senanayake, US vice-president of chemical development for BI.
Chemistries routinely practiced in the pharmaceutical setting include amide bond formations, common acid/base promoted hydrolytic reactions to access amide and carboxyl moieties, carbon-carbon bond formations (Grignard, Suzuki-Miyaura, Negishi, Sonagishira, Heck), oxidations, reductions (classical and asymmetric), halogenations, esterifications, alkylations, aminations, nitrations, and classical and enzymatic resolutions, according to Marlon Lutz, a process development and flow chemist with Regis Technologies.
“Advances in catalysis, including both chemical and biocatalysis, have been the most impactful for API synthesis,” asserts Senanayake. Specifically, he points to the design and discovery of new (chiral) phosphine ligands that have allowed many efficient transformations such as cross couplings and the installation of chiral centers to be performed on large scales (1-3).
Carbon-carbon bond forming organometallic chemistry is another chemistry worth highlighting, according to Stephen A. Munk, president of Ash Stevens, a division of Piramal Pharma Solutions. “Scalable palladium-catalyzed coupling reactions, such as Sonogashira and Suzuki reactions, allow for efficient carbon-carbon bond formation at the larger volumes required for API manufacturing,” he observes. (See an example in reference 4.)
In biocatalysis, the use of directed evolution technology has resulted in the engineering of highly efficient enzymes for a wider range of chemical reactions than ever before, according to Song. Multiple examples of biocatalysis in API synthesis on the commercial scale have been reported (5-6).
“With lower processing times, solvent volumes, and reduced waste streams, flow chemistry (continuous processing) has enabled processes to be operated more efficiently, safer, cleaner, cheaper, and faster,” Lutz states. In addition, process analytical technologies (PATs) have enabled flow chemistry processes to be executed with higher confidence and reproducibility and generate products that are of high purity and yield. Furthermore, FDA supports the use of a continuous flow approach for producing APIs.
“Many pharmaceutical chemical processes are still performed in batch vessels, which are strictly limited by the process conditions (e.g., boiling points of solvents at atmospheric pressure) and often require long processing times for heating/cooling of large batch reactors. There has, however, been an increasing expectation for safer, more efficient, cost effective and greener synthetic routes. Flow chemistry has attracted attention as realization of its numerous benefits for achieving this goal has spread,” Lutz adds.
In particular, flow chemistry is highly applicable for processes that require high mixing and heat/mass transfer, control of processes operating in the thermal runaway regime, and safely conducting hazardous chemistry that is difficult to handle in conventional batch reactors.
At BI, flow chemistry has been employed for reactions that would not be possible using conventional batch protocols, according to Song. “Several of our programs involving high-energy reagents (azides), unstable intermediates (organolithiums), and extreme reaction temperatures (low or high) have benefited from flow technology,” he comments. In one example, approximately one metric ton of a propargyl borolane reagent was manufactured in good yield and high quality using flow chemistry (7).
In addition, the ability to automate commercial flow reactors has impacted how process development is performed and translated into manufacturing, according to Lutz. “The use of flow chemistry enables process development and reaction optimization to be performed significantly more quickly than traditional approaches using batch vessels,” he explains. Employing PAT with flow reactor systems extensively reduces development times with elimination of the bottleneck of offline analysis (8).
Furthermore, translating flow processes from research-scale models to commercial scale is relatively simple; if the geometries and design of the flow reactor are maintained, the number of flow reactors can be increased to achieve the desired product output (‘numbering up’), according to Lutz. He also notes that many of the commercial-scale flow reactors are designed to offer enhanced mixing and heat/mass transfer phenomena when increasing throughput.
It is also worth noting, according to Lutz, that implementing flow chemistry can be beneficial for contract manufacturing organizations (CMOs) because they can easily use flow chemistry for problem steps that are low yielding, require harsh conditions, are medium- to high-risk due to the reaction conditions, or use excesses of expensive reagents.
It isn’t only advances in chemistry and processing technology that have improved API manufacturing. The evolution of a contemporary data-rich laboratory environment with new equipment, software, process modeling techniques, quality-by-design methodology, multidisciplinary collaborations, more sensitive analytical instruments, enhanced safety analyses using reaction calorimetery, accelerating rate calorimetry (ARC), and thermal screening units (TSus) is providing a deeper understanding of chemical processes and their predictability at scale, according to Munk.
“Today it is not only possible to improve yields and limit the formation of impurities; in-depth understanding of processes leads to better process control, safety, reliability, and robustness, along with improved product quality,” he explains. “It also allows for continuous improvement of the process and understanding where things fail and the consequences of the failure using statistical data without having to do hundreds of experiments,” Munk adds. New safety equipment/instrumentation and software allow for safer scale up of processes, while new laboratory reactor systems better model plant equipment and stirring conditions. A more multidisciplinary approach to process development looks at processes from more perspectives (modeling, statistically, engineering, safety, and environmental impact).
While catalysis and flow chemistry are having the greatest impact on API manufacturing, there are many other advances providing measurable improvements. More efficient, environmentally compatible, and cost-effective production-scale chromatography equipment, including simulated moving bed (SMB) and supercritical fluid chromatography (SFC), is one example, according to Munk.
Greater understanding of solid-state forms and genotoxic impurities are also important. Access to greater knowledge through rapid and effective solid form screening leads to the selection of more developable APIs (9). Identification of impurities and their sources makes it possible to develop more efficient, optimized processes with higher yields and purity profiles (10).
Highly potent and complicated drugs such as antibody-drug conjugates and proteolysis targeting chimera are more prominent in the industry and are requiring significant containment infrastructure, purification equipment, and experienced chemists, according to Munk. The existence of different potency categorization schemes and the need to ensure operator and environmental safety pose significant challenges (11).
Returning to specific chemistry examples, Song points to Knochel’s Turbo Grignard reagent as an important chemistry enjoying wide application in industry and academia. “This chemistry revolutionized the way in which Grignard reagents are generated. Due to its unique reactivity, Turbo Grignard offers benefits such as wider functional group compatibility and improved safety and cost-effectiveness for Grignard formation (12-13). Organozinc reagents have shown wider functional group compatibility as well, according to Marlon. (See reference 14 for an example.)
While the advances discussed above are indeed significant, challenges in API synthesis and manufacturing remain. Fortunately, further developments are ongoing and provide significant potential for the future. For example, useful methods for fluorination and trifluoromethylation (15-16), which are needed given that approximately 20% of drugs contain at least one fluorine atom, are allowing medicinal chemists to access novel structures for structure-activity relationship studies and to secure intellectual property for new drug candidates, according to Senanayake. These methods are not ready for large-scale application, however. More work is required in both academia and industry to address substrate scope, catalyst loading, and general practicality issues. Lutz also points to greener metal-catalyzed fluorinations as showing great promise for the replacement of common and harsh fluorinating reagents (17-18).
Direct functionalization of unactivated C-H bonds is another field showing promise for simplification of synthetic routes through reduction of the number of required steps, according to Lutz. He also points to palladium-catalyzed cyanations with potassium ferrocyanide (19) as providing convenient access to amides, amidines, esters, and carboxylic acids while eliminating the concerns associated with current cyanide-based reactions.
Much work is also being directed at the development of non-precious metal catalysis, which can reduce costs and toxicity and enable greener processes, according to Senanayake. He notes that significant strides have been made in this area in the past five years, with the development of nickel (Ni)- and iron-catalyzed sp2-sp3 couplings of particular interest to the pharmaceutical industry (20-21).
Microwave reactors, according to Munk, offer enhanced reaction times and enable transformations that will only work under microwave conditions. Photo-redox reactions, meanwhile, allow the use of the cheapest and cleanest energy source (i.e., solar power) for chemistry, according to Song. In addition, this technology can be combined with chemistry to deliver greener processes (22-23).
“API manufacturing requires not only effective chemical technologies, but seasoned, experienced process chemists who understand the necessary requirements for the development of GMP processes, including route selection, cost efficiencies, robustness, reaction mechanisms, environmental impact, and product quality, among other attributes,” asserts James M. Hamby, vice-president of business development for Ash Stevens. These process chemists many times develop and report interesting modifications, efficiency enhancements, and uses of established chemistries to effect large-scale transformations.
“Each process presents a unique set of challenges. No one chemistry or technology really stands out as above all the rest. That is why experienced chemists working in a multidisciplinary team deliver the best results,” Hamby concludes.
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