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Life Sciences Focus: Drug Delivery Flow Chemistry


reaction to full-scale production. Another victory in the ongoing battle against the bacteria!


References: 1) Evolution of antimicrobial resistance among Enterobacteriaceae (focus on extended spectrum -lactamases and carbapenamases, J. Lynch et al, Expert Opin. Pharmacother. 2013, 14, 199-210; Three decades of -lactamase inhibitors, S. Drawz et al, Clin. Microbiol. Rev.2010, 23, 160-201.


2) Meropenem/Vaborbactam: a review in complicated urinary tract infections, S. Dhillon, Drugs 2018, 78, 1259-1270. The first -lactamase inhibitor approved for clinical use was Clavulanic acid in the 1970s.


3) Discovery of a cyclic boronic acid -lactamase inhibitor (RPX7009) with utility vs class A carbapenemases, S. Hecker et al, J. Med. Chem. 2015, 58, 3682-3692; T. Eisenman, FDA approves new antibacterial drug, August 29th2017.


Dr John Studley, Scientific Director, Scientific Update


dichloromethyllithium at higher temperatures under flow conditions was demonstrated,9 Christian Schuster’s team at Patheon (Thermo Fisher Scientific), in collaboration with a wider group of industry experts,successfully utilized this technology, converting a lab-based model reaction into a continuous manufacturing process run on several-hundred-kilogram scale under full cGMP conditions in yields of 97% .10 The corresponding batch process proved unscalable under laboratory conditions. Ultimately several tonnes of Matteson product were prepared in a process validation flow campaign enabling FDA fast-track approval and facilitating rapid development of Vaborbactam. Key to the success of this work was a detailed investigation into the zinc chloride addition and developing conditions to prevent precipitated solids clogging the system – a mainstay of flow chemistry processes. In early development work, the process flowstream was quenched into a batch vessel containing the pre-cooled zinc Lewis acid.


issues with patients because regular administrations of the drug are not required.


Nanoencapsulation in cosmetic applications While much of the focus of nanoencapsulation and nanocarriers has been around pharmaceuticals and drug delivery systems, there are some areas within the cosmetics industry where they are also used. Some of the more common examples include delivering moisture in oil-based ointments and creams to increase the hydrating properties of the product. There are a number of commercial products that use nanocarriers to add such hydration properties to formulations and hydrate the skin when applied.


This quickly became a bottleneck for Abstract representation of drugs encapsulated in nanocarriers. (Image © iStock.com / writerfantast)


Another common nanoencapsulation approach is to encapsulate fragrances, where the nanocarrier vessel breaks upon application, releasing the fragrance and making it last longer. There are also many unstable cosmetic compounds, such as hydroquinone— a compound that is used to lighten skin — that oxidize rapidly in oxygen and moisture. By encapsulating such molecules, they can be applied on the skin and not undergo any unfavourable chemical reactions before they perform their intended function. There is also a growing trend to use nanocarriers to deliver cosmeceuticals — a cross-over area of pharmaceuticals and cosmetics that applies both therapeutic and cosmetic benefits


increasing throughput, however. Two engineering solutions to this problem were explored, a continuous loop quench (mimicking the batch process) and a continuous stirred tank (CSTR)- based cascade quench. In the loop quench, boronate adduct was fed into a circulating pre-cooled solution of zinc chloride with reaction temperature controlled by heat exchangers. The product solution was pumped out and consumed zinc salt was continuously replenished in the loop reactor to keep the molar ratio constant. In the CSTR approach, zinc chloride solution was constantly fed to the pre-cooled vessel, the product solution exiting the CSTR in a cascade system controlled by an overflow device. The loop reactor system was ultimately selected to move forward and enabled the reaction to be run at a higher temperature and with better diastereometric control.


By leveraging the advantages a continuous process can impart, including increased process control, energy efficiency and reduced processing times, Schuster’s team succeeded in taking a difficult, unscalable organometallic


4) Synthesis of biologically active boron-containing compounds, H. Zhou et al, Med. Chem. Commun. 2018, 9, 201-211; The versatility of boron in biological target engagement, A. Yudin et al, Nature Chem. 2017, 9, 731-742. The first boron-containing drug, Bortezomib (Velacade), was approved in 2003.


to the surface they are applied on. A range of nanocarriers are in use in this interdisciplinary field, including liposomes and other lipid-based carriers, niosomes and nanoemulsions, to name a few. These nanoencapsulation methods play a wide role in the cosmeceutical area, including hair care products for treating grey hair and hair loss (as well as other hair serums), anti-wrinkle creams,and in sunscreens. Identik, Origem, Nirvel, Chanel, Dior, Estée Lauder, Decorte and Sesderma are just a few of the big-name brands that currently utilize nanoencapsulation technologies to enhance their products.


In summary Overall, a number of companies


5) Homologation of boronic esters to -chloro boronic esters, D. Matteson et al, Organometallics, 1983, 2, 1529-1535; -halo boronic esters: intermediates for stereodirected synthesis, D. Matteson Chem. Rev. 1989, 89, 1535-1551.


6) Stability and reactivity control of carbenoids: recent advances and perspectives, V. Gessner, Chem. Commun. 2016, 52, 12011-12023.


7) Lithiation-borylation methodology and its application in synthesis, V. Aggarwal et al, Acc. Chem. Res. 2014, 47, 3174-3183.


8) Flow technology for the genesis and use of (highly) reactive organometallic reagents, R. Luisi et al, Chem. Eur. J. 2020, 26, 19-32; A perspective on continuous flow chemistry in the pharmaceutical industry, M. Baumann, M. Smith et al, Org. Process Res. Dev. 2020, ASAP 10.1021/ acs.oprd.9b00524.


9) Dichloromethyllithium: synthesis and application in continuous flow mode, J. Sedelmeier et al, Org. Lett. 2017, 19, 786-789.


Author:


10) Development of a continuous flow process for a Matteson reaction: from lab to full-scale production of a pharmaceutical intermediate, C. Schuster et al, Org. Process Res. Dev.2019, 23, 1069-1077.


Author details: Dr John Studley, Scientific Director Scientific Update Limited Maycroft Place, Stone Cross Mayfield TN20 6EW UK E: johns@scientificupdate.com


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Liam Critchley Freelance Chemistry and Nanotechnology Writer E: liam_critchley@hotmail. com


across the pharmaceutical and cosmetic sectors are now starting to utilize and reap the benefits of nanoencapsulation methods, and nanotechnology in general. It is likely that this trend will continue, and there will be more products in both sectors utilizing nanoencapsulation methods and other nanotechnology-based systemsin the years to come.


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