On-Demand Continuous Manufacturing of Ciprofloxacin in Portable Plug-and-Play Factories: Development of a Highly Efficient Synthesis for Ciprofloxacin

Abstract

The experimental approach taken and challenges overcome in developing a high-purity production (>100 g) scale process for the telescoped synthesis of the antibiotic ciprofloxacin is outlined. The process was first optimized for each step sequentially with regard to purity and yield, with necessary process changes identified and implemented before scaling for longer runs. These changes included implementing a continuous liquid–liquid extraction (CLLE) step and eliminating and replacing the base 1,8-diazabicyclo[5.4.0]­undec-7-ene (DBU) initially used in the ring-closure step due to DBU plausibly forming a decomposition side product that negatively impacted the final product purity. Process conditions were scaled 1.5–2-fold in order to enable the ultimate project goal of producing enough crude ciprofloxacin within 24 h to manufacture 1000 250 mg tablets. Working toward this goal, several production-scale runs were carried out to assess the reproducibility and robustness of the finalized process conditions, with the first three steps being run continuously up to 22 h and the last two steps being run continuously up to 10 h. The end result is a process with a throughput of ∼29 g/h (∼700 g/24 h) with a crude product stream profile of 94 ± 2% and 34 ± 3 mg/mL after five chemical transformations across four reactors and one continuous CLLE unit operation with each intermediate step maintaining a purity >95% by HPLC.

Impurity incorporation in solution crystallization: diagnosis, prevention, and control

“…6), before being implemented in end-to-end manufacturing. 27,38 While development was conducted based on a limited understanding of the mechanisms for impurity incorporation, an important part of the purification efficiency came from the selection of crystallization solvents that mitigated the co-precipitation of challenging impurities, and to the selection of wash steps to re-dissolve organic impurities and inorganic precipitates.…”

“…In the manufacturing of small-molecule pharmaceuticals, even a small number of synthesis steps can quickly lead to the generation of dozens of impurities, often with unknown composition or toxicological information. 26–30 Consequently, most recent examples of end-to-end synthetic pharmaceutical manufacturing involve a number of crystallization steps where the main role is to purify an intermediate product, limiting the accumulation of impurities along the main process stream. 25,26,31–38 Despite the widespread use of these purification steps, our understanding of how impurities incorporate in crystals is far behind, current models for predicting purity in solution crystallization are limited to a narrow design space, 25,28 and process design is still largely based on extensive solvent screenings and trial and error.…”

Understanding flow chemistry for the production of active pharmaceutical ingredients

“…Recent developments in API syntheses also include the flow synthesis of gefapixant citrate (MK-7264) ( Ren et al., 2020 ), ticagrelor ( Hugentobler et al., 2017 ), darunavir ( Leão et al., 2015 ), ciprofloxacin ( Armstrong et al., 2021 ), rufinamide ( Borukhova et al., 2016a ), among others.…”

PAT Implementation on a Mobile Continuous Pharmaceutical Manufacturing System: Real-Time Process Monitoring with In-Line FTIR and Raman Spectroscopy

“…Figure 1A describes the normal operating conditions for the five-step process, including the expected product concentrations. 31 The PAT setup for the PoD synthesis unit is shown in Figure 1B. Reaction steps 1−3 are telescoped and the material from step 3 is collected in a vessel prior to being processed in telescoped steps 4−5.…”

“…Additional TBAOH is introduced for hydrolysis of 7 in the fifth step to manufacture ciprofloxacin 8. The specifics on the synthesis conditions and the HPLC analytical method used for this work can be found in a previous publication 31 and in the Supporting Information for this manuscript.…”