INTRODUCTION
Today, flow chemistry is playing an increasingly important role in modern process chemistry. 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 research, development and manufacturing of new generation Active Pharmaceutical Ingredients (APIs) / High Potent Active Pharmaceutical Ingredients (HPAPIs).
Improved heat / mass transfer, improved impurities profiling, faster reactions, process intensification, easier scale-up & technology transfer (TT), Research & Development (R&D) cost saving, and reduction drug development-to-market timeframe are just some of the benefits to going flow in API synthesis. Additional advantage is that the small size of the micro-reaction technology (MRT) offers high surface-to-volume ratio which translates into high controllability of all process parameters (such as mixing, temperature, pressure, flow rate and residence time) by opening new scale-up opportunities to access novel process windows for cGMP manufacturing of APIs / HPAPIs (1, 2).
FHG GOES FLOW IN API SYNTHESIS
Responding to the rising number of new CDMO programs that require ever more specialized and niche chemistry, today Farmhispania Group (FHG) celebrates its 50th anniversary with launching of a new flow chemistry unit fully dedicated to research, development and industrialization of flow continuous processes for cGMP manufacturing of new generation APIs / HPAPIs.
Equipped with a cutting-edge R&D flowchem labs and today with opening of a new cGMP industrial-scale facility, FHG offers a fully-integrated flowchem CDMO platform by assuring a smooth, safe and optimized scale-up & TT – from early R&D feasibility study (GO/NO-GO study) runs to Proof-of-Scalability up to your first cGMP mid-scale and commercial production (1-250+ kg scale). A whole variety of flowchem R&D protocols for a wide range of chemical reactions – such as nitration, azide-chemistry, cyanide-chemistry, organometallic chemistry, bromination – have been successfully achieved at “Proof-of-Scalability” stage within FHG flowchem labs, ready to be exploited for scale-up and industrialization. In terms of challenging chemotypes, flow chemistry is heavily investigated to improve process chemistry metrics (such reaction yield, chemo-, regio-, stereo-selectivity and E-factor) and safety / environmental / quality profile of batch processes.
Figure 1. FHG FlowChem R&D Lab.
Figure 2. FHG FlowChem Industrial Plant.
FLOW CHEMISTRY RESEARCH AREAS IN FHG
Flow chemistry is undoubtedly the mainstream of the modern R&D pharmaceutical industry, and of FHG. The flow chemistry unit of FHG focuses on three main research areas: “Hazardous Chemistry”, “Novel Chemistry” and “Green Chemistry”.
The research area of “Hazardous Chemistry” attracted significant interest in flow chemistry community, since the moment that the most direct, atom-economic, and sustainable synthetic routes frequently require the use of highly reactive, often toxic and short-lived reagents (such e.g. BrCN, HCN, R-Li, R-MgX, N2H4, COCl2, CH2N2, CO, O3, etc.). These reagents are often valuable and exceptionally versatile building blocks for APIs / HPAPIs, but due to its intrinsic reactivity and instability, use of these hazard reagents significant challenges for safe scale-up, making these reactions not amenable on large-scale in batch modality.
Another flowchem research area of interest in FHG is to explore non-conventional tools such as bio-catalysis for synthesis of complex APIs / HPAPIs. A wide of selected enzyme class libraries (lipases, transaminases, hydrolases, oxidoreductases, glycosyltransferases, decarboxylases, aldolases, halogenases, etc.), are available at FHG for bio-catalyst high-throughput screening. From an application perspective, halogenating enzymes are increasingly attracting attention for biocatalytic C−H functionalization. Despite its importance for synthetic chemistry (especially for aryl- bromides and chloride – being important building blocks for C-C bond formation for a great number of APIs via cross-coupling chemistry), selective introduction of halogens using conventional approaches often remains challenging, whereas biocatalysis offers excellent catalyst-controlled selectivity without requiring protecting groups or hazardous reagents.
Under the auspices of green chemistry and Operations Excellence Program, FHG is also partnering with pharma & biotech customers in research, development and industrialization of 2nd / 3rd generation processes of commercial APIs / HPAPIs via continuous manufacturing (CM), with aim to develop cost-effective and green-by-design synthetic routes.
Aiming to broaden the potential of flow chemistry in API synthesis, FHG is opening new partnership opportunities for the development of new CDMO business. FHG is approaching new flowchem research areas, through external research collaboration with industry and Contract Research Organizations (CROs) for expanding its own flowchem toolbox. Development of continuous flow Grignard reactions, development of continuous flow hydrogenation over resin supported catalyst, and development of enzyme-immobilization technologies are just a few examples of new research area ongoing within FHG.
REFERENCES AND NOTES
- M. Berton; J. M. de Souza; I. Adbiaj; D. T. McQuade; D. R Snead. J. Flow Chem. 2020, 10, 73. Scaling continuous API synthesis from milligram to kilogram: extending the enabling benefits of micro to the plant.
- Z. Wen; T. Noël. Chem. Sci. 2023, 14, 4230. A field guide to flow chemistry for synthetic organic chemists.
Contact
Jacopo Buzzanca, PhD MBA
CDMO NBD Manager
Farmhispania Group
E-Mail: jbuzzanca@fhrt.com
Web: www.farmhispaniagroup.com
