- Title
- Exploiting continuous flow technology to develop synthetic processes for active pharmaceutical ingredients: prilocaine and betrixaban
- Creator
- Sagandira, Mellisa Brenda
- Subject
- Pharmaceutical technology
- Subject
- Drug development
- Subject
- Pharmaceutical biotechnology
- Date Issued
- 2024-12
- Date
- 2024-12
- Type
- Doctoral theses
- Type
- text
- Identifier
- http://hdl.handle.net/10948/69464
- Identifier
- vital:77259
- Description
- The dilemma of providing affordable health care has long haunted African countries due to the continuously growing disease burden as the population increases. Africa accounts for only 3 % of global drug production and imports over 90 % of its life saving medicines at a yearly cost of US$14 billion according to the African Development Bank (AfDB). Attaining Africa’s Agenda 2063, Universal Health Coverage (UHC) and Sustainable development Goal 3 (SDG3) aspirations of ensuring healthy and well-nourished citizens remain difficult given this situation. This over-dependence on imports has led to drug shortages, high pricing, poor quality medicines and unguaranteed supply chains, thus there still remains an unmet need. The advent of the COVID-19 pandemic worsened this situation as many countries curbed exports resulting in a crisis across the continent. Africa experienced high demand of medicines compared to prepandemic level, which threatened the health care of the continent. This situation can be addressed by establishment of local pharmaceutical manufacturing capability through adoption of advanced manufacturing technologies such as continuous flow chemistry. In this research, we therefore seek to exploit continuous flow chemistry, an enabling technology to develop safe and efficient synthetic processes for active pharmaceutical ingredients: prilocaine and betrixaban as case studies. To the best of our knowledge there is no reported work on synthetic processes towards prilocaine and betrixaban under continuous flow conditions, thus this research extensively unearthed interesting continuous flow processes towards these APIs. In a broader view, establishment of local APIs production will ease Africa’s over-dependence on imports, which will in turn address issues such as drug shortages, poor quality and high pricing. This work aims to demonstrate how continuous flow technology can be useful for the establishment of local APIs manufacturing, which will inherently revolutionize medicines availability, affordability and accessibility to the greater population. Chapter one begins with a brief overview on Africa’s disease burden and pharmaceutical supply chain. Continuous flow chemistry is introduced with its benefits and limitations discussed. Lastly a mini review of examples of APIs synthesised in continuous flow is presented. In chapter two, we demonstrate how continuous flow technology can be exploited to develop synthetic processes towards prilocaine as our first case study. This chapter clearly demonstrates how highly exothermic nitration reactions can be safely handled by using continuous flow systems. Additionally, the use of a micro structured mixer facilitated biphasic nitration of toluene to be carried out with enhanced mass transfer, which inherently led to improved selectivity of ortho-nitrotoluene (preferred isomer) to 79 % compared to 59 % achieved in batch mode. A two-step synthesis of ortho-toluidine via biphasic nitration of toluene and nitroreduction was demonstrated with the incorporation of a Zaiput liquid/liquid separator to facilitate in-line separation. Comprehensive optimisation studies were carried out in flow. Prilocaine was synthesised in 74 % overall yield in a 13.6 min residence time for all processes. In chapter three, we demonstrate how continuous flow technology can be exploited to develop synthetic processes towards betrixaban. Synthetic routes towards betrixaban feature two amide bond formation transformations. Pleasingly, we explored multistep chemistry to develop amide synthesis protocols in flow without interruption for work up and isolation. An overall yield of 92 % was achieved to get to key intermediate to betrixaban in 8 min total residence time. Chapter four demonstrates the robustness of developed amide synthesis protocols, a key transformation in synthetic routes towards prilocaine and betrixaban in continuous flow systems. A total of 22 amides were synthesised via flow multistep processes with isolated yields greater than 82 %. All the compounds were characterized using infrared spectroscopy (IR), and nuclear magnetic resonance (NMR). Quantification of the reaction mixtures were carried out using highperformance liquid chromatography (HPLC) and gas chromatography (GC).
- Description
- Thesis (PhD) -- Faculty of Science, School of Biomolecular & Chemical Sciences, 2024
- Format
- computer
- Format
- online resource
- Format
- application/pdf
- Format
- 1 online resource (328 pages)
- Format
- Publisher
- Nelson Mandela University
- Publisher
- Faculty of Science
- Language
- English
- Rights
- Nelson Mandela University
- Rights
- All Rights Reserved
- Rights
- Open Access
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NMU School of BioMolecular and Chemical Sciences
| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | SOURCE1 | SAGANDIRA, M.pdf | 13 MB | Adobe Acrobat PDF | View Details Download |