Exploiting continuous flow technology to develop synthetic processes for active pharmaceutical ingredients: prilocaine and betrixaban
- Authors: Sagandira, Mellisa Brenda
- Date: 2024-12
- Subjects: Pharmaceutical technology , Drug development , Pharmaceutical biotechnology
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10948/69464 , 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). , Thesis (PhD) -- Faculty of Science, School of Biomolecular & Chemical Sciences, 2024
- Full Text:
- Date Issued: 2024-12
- Authors: Sagandira, Mellisa Brenda
- Date: 2024-12
- Subjects: Pharmaceutical technology , Drug development , Pharmaceutical biotechnology
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10948/69464 , 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). , Thesis (PhD) -- Faculty of Science, School of Biomolecular & Chemical Sciences, 2024
- Full Text:
- Date Issued: 2024-12
Strategies employed by teachers to assist Grade 4 learners transition from mother tongue instruction to English as a medium of instruction
- Authors: Butler, Cynthia Desiree
- Date: 2021-01
- Subjects: English language -- Grammar -- Study and teaching , English language -- Study and teaching -- Foreign speakers
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10353/20035 , vital:45029
- Description: In most South African schools, there is a transition period, where lower primary learners receive instruction in their mother tongue from grades 1-3 and from grade 4 onwards, English becomes the medium of instruction. This study explored how learners in primary schools in Grade 4 learn through the medium of English, since IsiXhosa is their home language and they come from a community of pre-dominantly IsiXhosa speakers where English is seldom heard or spoken. The study is concerned with the language and literacy practices at this crucial transition, and investigated to what extent learners in the Grade 4 have learnt / been taught / have developed sufficient basic inter-personal communication skills, BICS, (Cummins, 2000), in isiXhosa to make the switch to learning all subjects in English. The theoretical frameworks adopted for this study was Cummins Language theories. Within this study an interpretive paradigm aligned with the qualitative approach and the case study design for understanding the phenomena, were adopted. The study covered three primary schools which were purposively selected. The participants comprised of six female teachers teaching Life Skills in Grade 4 from five mainstream schools were also purposively selected. Semi structured interviews, observation and document analyses were used as data collection instruments. A qualitative thematic approach was used for data analyses and the emerging results were organised into different themes reflecting participant’s responses. The findings revealed that teachers did not use lesson plans as they have indicated. Even though literature emphasises the importance of lesson planning, teachers find it tedious to plan. It was established that no assessment tasks were done when the lesson was concluded. Effective teaching without valid and reliable assessment tasks would result in meaningless teaching and learning interactions. It was revealed that teachers used teaching aids, but only a few. The information demonstrated that teachers did not code switch to assist with learner understanding. Instead, they presented their lessons in English which hampered learning. The study discovered that teachers used the old traditional style of teaching, instead of learner-centred instruction, which is interactive and participatory. The study exposed that the biggest challenges learners encountered, was the language of teaching and learning, English. However, the findings established that learners where unable to understand and express themselves in English. English lessons had minimal learner participation, because learners did not have the necessary competence and English was not their home language. The study further revealed that the English language leads to a barrier of effective learning and placed learners at a disadvantage. The findings further suggested that a lack of resources had an impact on teaching and learning which affected learners’ acquisition and understanding of the medium of instruction. The findings claimed that slow and progressed learners exist in classrooms and need individualised and specialised teaching. It was found that parental involvement, translation, learner participation, group work and teaching aids assisted with the challenges teachers encounter during transitioning in the subject Life Skills. It is recommended that the school develop a structured programme to provide support and assistance for teachers with lesson planning. Assessment task should be included in each lesson and should be viewed as an essential part of teaching and learning. Teachers should make use of multiple and a variety of teaching aids. Code switching and translation should be used, as it assists with understanding, accuracy and clarity. An appropriate mix of teaching styles should be used, to reach all leaners in a classroom. Teachers can improve learners English, by incorporating learners’ home language, code-switching and teaching aids in class. Slow and progressed learners could be assisted by using a variety of teaching materials, individual attention, remedial education, peer tutoring, differentiated teaching and curriculum adaptation. A structured learning support programme providing learning support for learners with barriers to learning, can be utilised. It is recommended that parents be involved in their children’s learning. The schools should set up effective monitoring and support mechanism for teachers in order to ensure that quality teaching and learning takes place in schools. Regular monitoring and evaluation by the DoE might assist to support teachers. A suggested framework of strategies in Life Skills, based on the findings of the study and extensive literature review, should contribute and assist with transitioning in Grade 4 in schools. , Thesis (DPhil) -- Faculty of Education, 2021
- Full Text:
- Date Issued: 2021-01
- Authors: Butler, Cynthia Desiree
- Date: 2021-01
- Subjects: English language -- Grammar -- Study and teaching , English language -- Study and teaching -- Foreign speakers
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10353/20035 , vital:45029
- Description: In most South African schools, there is a transition period, where lower primary learners receive instruction in their mother tongue from grades 1-3 and from grade 4 onwards, English becomes the medium of instruction. This study explored how learners in primary schools in Grade 4 learn through the medium of English, since IsiXhosa is their home language and they come from a community of pre-dominantly IsiXhosa speakers where English is seldom heard or spoken. The study is concerned with the language and literacy practices at this crucial transition, and investigated to what extent learners in the Grade 4 have learnt / been taught / have developed sufficient basic inter-personal communication skills, BICS, (Cummins, 2000), in isiXhosa to make the switch to learning all subjects in English. The theoretical frameworks adopted for this study was Cummins Language theories. Within this study an interpretive paradigm aligned with the qualitative approach and the case study design for understanding the phenomena, were adopted. The study covered three primary schools which were purposively selected. The participants comprised of six female teachers teaching Life Skills in Grade 4 from five mainstream schools were also purposively selected. Semi structured interviews, observation and document analyses were used as data collection instruments. A qualitative thematic approach was used for data analyses and the emerging results were organised into different themes reflecting participant’s responses. The findings revealed that teachers did not use lesson plans as they have indicated. Even though literature emphasises the importance of lesson planning, teachers find it tedious to plan. It was established that no assessment tasks were done when the lesson was concluded. Effective teaching without valid and reliable assessment tasks would result in meaningless teaching and learning interactions. It was revealed that teachers used teaching aids, but only a few. The information demonstrated that teachers did not code switch to assist with learner understanding. Instead, they presented their lessons in English which hampered learning. The study discovered that teachers used the old traditional style of teaching, instead of learner-centred instruction, which is interactive and participatory. The study exposed that the biggest challenges learners encountered, was the language of teaching and learning, English. However, the findings established that learners where unable to understand and express themselves in English. English lessons had minimal learner participation, because learners did not have the necessary competence and English was not their home language. The study further revealed that the English language leads to a barrier of effective learning and placed learners at a disadvantage. The findings further suggested that a lack of resources had an impact on teaching and learning which affected learners’ acquisition and understanding of the medium of instruction. The findings claimed that slow and progressed learners exist in classrooms and need individualised and specialised teaching. It was found that parental involvement, translation, learner participation, group work and teaching aids assisted with the challenges teachers encounter during transitioning in the subject Life Skills. It is recommended that the school develop a structured programme to provide support and assistance for teachers with lesson planning. Assessment task should be included in each lesson and should be viewed as an essential part of teaching and learning. Teachers should make use of multiple and a variety of teaching aids. Code switching and translation should be used, as it assists with understanding, accuracy and clarity. An appropriate mix of teaching styles should be used, to reach all leaners in a classroom. Teachers can improve learners English, by incorporating learners’ home language, code-switching and teaching aids in class. Slow and progressed learners could be assisted by using a variety of teaching materials, individual attention, remedial education, peer tutoring, differentiated teaching and curriculum adaptation. A structured learning support programme providing learning support for learners with barriers to learning, can be utilised. It is recommended that parents be involved in their children’s learning. The schools should set up effective monitoring and support mechanism for teachers in order to ensure that quality teaching and learning takes place in schools. Regular monitoring and evaluation by the DoE might assist to support teachers. A suggested framework of strategies in Life Skills, based on the findings of the study and extensive literature review, should contribute and assist with transitioning in Grade 4 in schools. , Thesis (DPhil) -- Faculty of Education, 2021
- Full Text:
- Date Issued: 2021-01
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