INTRODUCTION
Today, flow chemistry is playing an increasingly important role in the modern API process chemistry; A confluence of factors is driving the need for a paradigm shift in API manufacturing strategies in pharmaceutical and CDMO industry, where for over 100 years have long been carried out using batch-wise operations. Movement towards tailor-made drug therapy, rising generics competition, dramatically higher clinical trial costs and timelines, the shift away from blockbusters to niche products, the growing number of candidates with accelerated development designations (Fast Track, Breakthrough Therapy, Orphan Drug) and, last but not least, the rising phenomenon of “pharmaceutical nationalism” in the Western Countries post COVID-19 pandemic is catalyzing the momentum and magnitude of flow chemistry adoption as a novel toolbox for chemical development and cGMP manufacturing of new generation APIs / HPAPIs.
In this article we focused our discussion only on a recent flowchem case study successfully achieved in FHG. The aim of this case study is to discuss the application of flow technology for the genesis and use of organolithium intermediates for the synthesis of a valuable cGMP advanced intermediate (Adv. IM) of a custom API under late-stage clinical development.
FLOW CHEMISTRY AS ESSENTIAL TOOLBOX FOR TODAY’S AND TOMORROW’S PHARMACEUTICAL INDUSTRY
The most direct, atom-economic, and sustainable synthetic routes frequently require the use of highly reactive, often toxic and short-lived reagents. Organo-metallic bases, Halogens, Azide, Diazomethane, Phosgene are valuable and exceptionally versatile reagents for synthesis of several Adv. IMs of critical APIs / HPAPIs. Due to their highly reactive nature and/or reaction harsh conditions profile, utilizing of these energetic materials are often problematic and impose significant challenges (or even hindered) for a safe scale-up in a traditional batch process modality. Flow chemistry provides a viable platform for use of these reagents on large-volume scale, expanding process chemistry’s horizon and opening scale-up possibilities towards reactions at high temperatures/pressures (novel process windows) and for ultrafast, exothermic reactions (flash chemistry).
The concern toward the utilization of hazardous materials on large-scale is not only related to their technical manufacturing issues but also to their transportation and on-site storage. In addition, from a big-picture perspective, COVID-19 pandemic and today geopolitical tensions have brought even greater attention to CM in the pharmaceutical industry for accelerate the glocalization movement of drug substances (DSs) & drug products (DPs) manufacturing from Asia (China and/or India) to Western countries, especially to Europe. Owing to the US administration’s trade war with China and calling of European Commission for fast-track approval of alternate suppliers of critical drugs, CM is seen as a pivot point for the today’s and tomorrow’s pharmaceutical industry.
GO FLOW IN API SYNTHESIS WITH FHG
Among several flowchem research programs underway at FHG, the utilization of organolithium bases in flow for API synthesis remains one of the core research topics of the industry. Although scale-up and transfer to large-scale industrial settings of organo-lithium reactions on batch modality have not seldomly been limited by safety concerns, the requirement for cryogenic temperatures, and functional group incompatibilities. Under the auspices of green chemistry, the revival of this flowchem research area arose from the possibility of combining the strengths of micro-reactors to achieve organolithium chemistry reactions more industrial- and eco-friendly than current batch processes. Improved heat/mass transfer, improved impurities profiling, faster reactions, process intensification, easier scale-up & TT, R&D cost saving, and reduction drug development-to-market timeframe are just some of the benefits of organo-lithium reactions in flow continuous modality.
Scale-up and technology transfer of a recent flowchem example of cryogenic organometallic reactions within FHG are described. Key learnings are offered from the practical perspective of FHG, highlighting a collaborative approach and partnership with sponsor company that allowed a successful execution with ambitious timelines for a rapid scale-up and right-first-time cGMP manufacturing of a cGMP Adv. IM of a new custom API under late-stage clinical development. The synthesis of this ketone intermediate (4) involved in a sequential deprotonation/lithium−halogen exchange mediated by methyllithium and n-butyllithium followed by a coupling reaction with an ester (2) (Figure 1). Flow chemistry was identified as a useful tool to scale-up two of these reactions for the following reasons: (A) higher yield and purity: precise control of key parameter such as residence time, mixing and temperature allow to handle the desired highly reactive transient intermediate (3) and minimize the formation of unwanted impurities (14 % yield increase from batch to flow); (B) scalability: performing these reactions in flow enable cryogenic reactions to be run at higher temperatures (33 ºC higher in flow), more suitable temperature for industrial manufacturing; (C) energy saving: long addition times, due to highly exothermic reaction, in batch would require maintaining a large volume (> 1000 L) of reaction mixture at cryogenic temperature but, in continuous modality, the same throughput is achieved using a reactor with internal volume < 5 L, reducing the energy input required; (D) safety: smaller reactor volume in flow decreases the risk of uncontrolled situations against events such thermal runaway, blowout or even vessel rupture.
Ketone (4) transfer was performed by the R&D FlowChem Unit using HNPM magnetic coupled gear pumps controlled by Flowlink controller through Bronkhorst mass flow meters (Figure 2A). The flow reactor was designed and built in-house using SS316L tubing (Figure 2B). Temperature was measured in-line for each stream before both T-junctions and tailor-made precooling heat exchangers were built to achieve required heat transfer efficiency at lab scale flow rate (being mass transfer that most influences heat transfer at low flow rate). The reactor was simply cooled by submerging the reactor in a thermostatic bath filled with isopropanol at -30 ºC (Figure 2C). We decided to use commercially available Koflo Stratos static tube mixer, placed after each T-junctions, to facilitate mixing scale-up. Fouling or clogging were detected by in-line pressure sensors. Outcome stream quench was done in batch (Figure 2C) because in-line quench does not offer any substantial advantage and further workup operations have been already developed in batch.
The feasibility of this process was demonstrated at R&D lab scale, 230 g of ketone (4) were generated using an 83 mL internal volume flow reactor (Figure 2B), which correspond to 62.4 g/h throughput. To match the throughput required for manufacturing campaign, a multi-purpose industrial flow skid of 4.58 L internal volume (Figure 2D) was careful designed and built. Pilot batches of 10’s kg were done in the same skid but shorter running time to demonstrate that the industrial conditions allow to achieve similar chemical performances.
THE FUTURE OF FLOW CHEMISTRY
Since the advent of flow chemistry in the modern pharmaceutical industry, we have been witnessing a renaissance of biocatalysis, photocatalysis and electrochemistry research area as non-conventional synthetic tools for drug discovery and development. These novel chemistry platforms have received a plethora of attention due to the increased mass and heat transfer characteristics, the possibility to increase process safety, and the potential to implement automation protocols and process analytical technology. Taking advantage of these aspects, nowadays chemists and chemical engineers have capitalized on expanding the chemical space available on large-scale with benefits of accessing to complex API scaffolds with synthetic routes easily and seamless transferable from mg-scale medicinal chemistry labs to pilot and commercial facility on multi-kg scale (1).
Continuous crystallization is another research area in advancement in the industry (2). Traditional batch crystallization can lead to inconsistencies in particle size, which is a major concern in API production. Technological advancements such as real-time monitoring using sensors, advanced control algorithms, and the development of new crystallizer designs have significantly improved the efficiency and applicability of continuous crystallization processes. Their integration with continuous reactions can streamline API synthesis, reducing the need for intermediate isolation and purification, decreases the risk of contamination, and enhances process safety. By combining these steps into a seamless workflow, CDMOs can achieve higher levels of quality and cost-effectiveness.
Although the lack of off-the-shelf equipment for scale-up (synthesis and crystallization) and of trained staff are still making slow the transition to continuous manufacturing (3), these new vibrant chemistry research areas have become the basis for thinking and doing today chemistry (4), and have to be seen as a pivot point for development of the tomorrow’s pharmaceutical industry.
Figure 1. Scheme of the two sequential reactions run in flow.
Figure 2. Left: flow system used at lab scale: (A) dosing system; (B) flow reactor; (C) flow reactor outcome quenched in batch. Right: (D) multi-purpose industrial flow skid.
REFERENCES AND NOTES
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- J. Orehek; D. Teslic; B. Likozar. Org. Process Res. Dev. 2021, 25, 16. Continuous Crystallization Processes in Pharmaceutical Manufacturing: A Review.
- C. A. Hone; C. O. Kappe. Chemistry-Methods 2021, 1, 454. Towards the Standardization of Flow Chemistry Protocols for Organic Reactions.
- (a) J.-C. M. Monbaliu; J. Legros. Lab Chip 2023, 23, 1349. Will the next generation of chemical plants be in miniaturized flow reactors?; (b) L. Capaldo; Z. Wen; T. Noël. Chem. Sci. 2023, 14, 4230. A field guide to flow chemistry for synthetic organic chemists.
