DIAGNOSTICS
experiments for the commercial manufacture of ciprofloxacin , an antibiotic , and other APIs . 3 , 4
Finally , there is a strong desire among pharmaceutical companies to improve environmental sustainability of manufacturing processes , in part by implementing Green Chemistry techniques . One tool used by process chemists to measure sustainability is process mass intensity ( PMI ), which is the ratio of the total mass of materials used to make 1 kg of a product .
Pharmaceutical manufacturing , with a PMI usually well above 100 - and between 2,000 and 25,000 for biologics5 - is the worst among all chemical manufacturing sectors . ( For comparison , oil production has a PMI between five and ten .) Continuous flow chemistry , as one way to reduce PMI and improve sustainability , is a focus area identified by the ACS Green Chemistry Institute Pharmaceutical Roundtable .
Continuous flow for DTT
The original batch process to DTT requires four steps , includes a bis-epoxide intermediate that is carcinogenic , mutagenic and volatile ( Figure 1 ). 6 For this reason , the reaction is done under mild conditions at low temperature to prevent the exposure to hazardous vapours . Under these controlled conditions , the reactions are slow , typically taking several hours to complete , and reaction yield is low .
BioVectra has been making DTT for 40 years . The company has developed a new continuous flow process , which greatly diminishes the safety hazard associated with the bis-epoxide , while optimising temperature , stoichiometry and residence time leading to process intensification .
An intensified telescoped continuous flow synthesis of DTT , using only three steps , has been developed at lab scale ( Figure 2 ). The toxic bisepoxide intermediate is generated and consumed during the first two steps without isolation , greatly improving safety and allowing the reactions to occur under increased temperature and pressure , thus increasing the rate of reaction .
The conditions for each step were optimised as one continuous process . The highest yield achieved of the final deprotection step ( 93 %) occurred in acidic conditions , using methanol as solvent , at 110 ° C , and under pressure which was unachievable with a batch process .
This telescoped continuous flow synthesis produced DTT with yields ranging from 74 % to 84 % ( 54-67 % isolated ) at a rate of 15.9 g / hour , at a scale of 10 – 100 g . This is vastly superior to the reported yield of the conventional batch process ( 36 %). The reaction conditions led to a relatively simple equipment set-up compared to a batch process .
Conclusion
A proof of concept that traditional batch production of bioreagents can be reassessed with continuous flow technology was presented , which could lead to significant benefits . A widely used 40-year-old synthetic process for a common bioreagent was optimised in a lab environment to a process that is much safer and has been intensified to result in shorter reaction times and higher yields .
Even though a compound has been synthesised the same way for decades using a batch process , it might not be the most efficient method to use . Continuous improvement , using new technology , can help improve safety and attain more sustainable drug synthesis .
While there will still be reactions that are better done in batch , flow chemistry should be viewed as a complementary set of tools to address , among other limitations , the need for flexibility and speed in responding to supply chain disruptions . Perhaps most significantly , this type of flow chemistry opens the door to a decentralised supply chain and more localised production at smaller scales . ●
References 1 : M . P . Socal et al ., Am . J . Public Health . 2021 , 111 ( 4 ): 635 – 639 2 : https :// www . fda . gov / news-events / press-announcements / coronavirus-covid-19-update-fda-takes-further-steps-help-mitigatesupply-interruptions-food-and 3 : G . Capellades et al ., Org . Process Res . Dev . 2021 25 ( 7 ): 1534 – 1546 4 : L . Rogers et al . Org . Process Res . Dev . 2020 ; 24:2183 – 2196 5 : K . Budzinski , M . Blewis , P . Dahlin , D . D ’ Aquila , J . Esparza , J . Gavin et al . N Biotechnol 2019 ; 49:37 – 42 6 : G . M . Whitesides et al ., J . Org . Chem . 1977 ; 42:332 – 338
Jean-François Vincent-Rocan
DIRECTOR , COMPLEX CHEMISTRY
BIOVECTRA k + 1 902 566 9116 J jvincent-rocan @ biovectra . com j www . biovectra . com
Figure 2 - Telescope synthesis of DTT with minimum unit operations
28 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981