Co-crystal formation of pharmaceutical and veterinary tranquilizer molecules
- Mngwengwe, Bongeka Naledi Precious
- Authors: Mngwengwe, Bongeka Naledi Precious
- Date: 2024-10-11
- Subjects: Cocrystal , Benzodiazepines , Mechanical chemistry , Midazolam , Tranquilizing drugs
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/464532 , vital:76519
- Description: Midazolam, a 1,4-benzodiazepine derivative is commonly used to treat anxiety, insomnia and may be used as a sedative in anaesthesia as it has calming, anti-convulsant and muscle relaxant properties. Midazolam has a rapid onset but a short duration of action resulting in fewer adverse effects. Midazolam also has the potential to form insoluble crystalline precipitates in pharmaceutical dosage forms such as syrups and solutions, which is a challenge in formulation and process development activities. The primary goal of this research was to prepare multicomponent crystals of midazolam free base, specifically targeting interactions with coformers structurally similar to methyl paraben. Key preparation techniques included neat grinding, liquid-assisted grinding, and slow evaporation. The resulting solid forms were characterized using Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), and powder X-Ray Diffraction (PXRD). In addition, Single-Crystal X-Ray Diffraction (SCXRD) was used to elucidate detailed structural information on the novel multicomponent crystals formed. Successful preparation of midazolam free base from the hydrochloride salt was confirmed through FTIR, DSC, and PXRD analysis. Different co-crystals and salts of midazolam with coformers such as salicylic acid (SA), benzoic acid (BA), 3-hydroxybenzoic acid (3-HBA) and p-aminobenzoic acid (PABA) were synthesized and characterized. The structure of the single crystal obtained from a veterinary tranquilizer solution was solved and found to be a salt that had formed between midazolam free base, midazolam HCl, and methyl paraben. This finding inspired further investigation of similar multicomponent crystals of midazolam and methyl paraben analogues. This study demonstrated the effectiveness of both mechanochemical and slow evaporation methods for the preparation of multicomponent crystals. PXRD and DSC provided insights into the stability and purity of the crystals that had formed and the differences in melting points and PXRD patterns were particularly important in this regard. Differences in FTIR spectra were used to distinguish between different solid forms and to confirm the successful formation of new solid forms. Extensive searches in the Cambridge Structural Database (CSD) confirmed that the multicomponent crystals of midazolam, such as MDZ‧SA, MDZ‧BA, MDZ‧3-HBA, and MDZ‧PABA, had not previously been reported, highlighting the novelty of these findings. The research successfully isolated and characterized several novel multicomponent crystals of midazolam, demonstrating the potential of mechanochemistry and solvent evaporation techniques in the development of pharmaceutical and veterinary medicinal applications. These findings contribute to the understanding of cocrystal formation and provide a foundation for future studies in which the stability and efficacy of midazolam-based formulations can be evaluated. , Thesis (MSc) -- Faculty of Science, Chemistry, 2024
- Full Text:
- Date Issued: 2024-10-11
- Authors: Mngwengwe, Bongeka Naledi Precious
- Date: 2024-10-11
- Subjects: Cocrystal , Benzodiazepines , Mechanical chemistry , Midazolam , Tranquilizing drugs
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/464532 , vital:76519
- Description: Midazolam, a 1,4-benzodiazepine derivative is commonly used to treat anxiety, insomnia and may be used as a sedative in anaesthesia as it has calming, anti-convulsant and muscle relaxant properties. Midazolam has a rapid onset but a short duration of action resulting in fewer adverse effects. Midazolam also has the potential to form insoluble crystalline precipitates in pharmaceutical dosage forms such as syrups and solutions, which is a challenge in formulation and process development activities. The primary goal of this research was to prepare multicomponent crystals of midazolam free base, specifically targeting interactions with coformers structurally similar to methyl paraben. Key preparation techniques included neat grinding, liquid-assisted grinding, and slow evaporation. The resulting solid forms were characterized using Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), and powder X-Ray Diffraction (PXRD). In addition, Single-Crystal X-Ray Diffraction (SCXRD) was used to elucidate detailed structural information on the novel multicomponent crystals formed. Successful preparation of midazolam free base from the hydrochloride salt was confirmed through FTIR, DSC, and PXRD analysis. Different co-crystals and salts of midazolam with coformers such as salicylic acid (SA), benzoic acid (BA), 3-hydroxybenzoic acid (3-HBA) and p-aminobenzoic acid (PABA) were synthesized and characterized. The structure of the single crystal obtained from a veterinary tranquilizer solution was solved and found to be a salt that had formed between midazolam free base, midazolam HCl, and methyl paraben. This finding inspired further investigation of similar multicomponent crystals of midazolam and methyl paraben analogues. This study demonstrated the effectiveness of both mechanochemical and slow evaporation methods for the preparation of multicomponent crystals. PXRD and DSC provided insights into the stability and purity of the crystals that had formed and the differences in melting points and PXRD patterns were particularly important in this regard. Differences in FTIR spectra were used to distinguish between different solid forms and to confirm the successful formation of new solid forms. Extensive searches in the Cambridge Structural Database (CSD) confirmed that the multicomponent crystals of midazolam, such as MDZ‧SA, MDZ‧BA, MDZ‧3-HBA, and MDZ‧PABA, had not previously been reported, highlighting the novelty of these findings. The research successfully isolated and characterized several novel multicomponent crystals of midazolam, demonstrating the potential of mechanochemistry and solvent evaporation techniques in the development of pharmaceutical and veterinary medicinal applications. These findings contribute to the understanding of cocrystal formation and provide a foundation for future studies in which the stability and efficacy of midazolam-based formulations can be evaluated. , Thesis (MSc) -- Faculty of Science, Chemistry, 2024
- Full Text:
- Date Issued: 2024-10-11
From more sustainable isocyanide-based multicomponent reactions to spiro-heterocyclic compound syntheses
- Authors: Salami, Sodeeq Aderotimi
- Date: 2023-10-13
- Subjects: Passerini reaction , Isocyanides , Isothiocyanate , Mechanical chemistry , Organic reaction
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/432229 , vital:72853 , DOI 10.21504/10962/432229
- Description: The global pharmaceutical industry has undergone profound transformations in the past two decades in the search for new drugs. For this reason, most pharmaceutical companies made significant investments not only in the development of new drugs but new methodologies. Modern drug development is confronted with the challenge of developing chemical reactions that are highly capable of providing most of the elements of structural complexity and diversity with the fewest possible synthetic steps for the specific target with the most intriguing properties. The discovery of more sustainable, environmentally friendly reactions capable of forming multiple bonds in a single step has been a challenge in organic synthesis over the years. Many organic chemists have recently started focusing on creative ways of reducing environmental pollution. The use of hazardous solvents has been reduced or eliminated in research to limit harm to both people and the environment. The pursuit of this goal has drawn many organic chemists to the study of various sustainable synthetic techniques including catalysis, aqueous organic reactions and mechanochemistry. The scope of this thesis was to apply sustainable techniques to design multicomponent synthetic protocols for the Passerini reaction and further apply these new protocols to construct spiro-heterocyclic compounds, all based on green chemistry principles. There is a need to develop rapid, efficient, and versatile strategies for the synthesis of bioactive molecules via multicomponent reactions. This project tried to avoid some of the pitfalls of traditional approaches, such as toxicity, low yield, long reaction times, harsh conditions, experimental complexity, and limited functionalization scope. This was achieved by focussing on the use of isonitriles and isothiocyanates as key reactive intermediates, and making extensive use of aqueous reaction conditions, mechanochemistry and microwave activation. , Thesis (PhD) -- Faculty of Science, Chemistry, 2023
- Full Text:
- Date Issued: 2023-10-13
- Authors: Salami, Sodeeq Aderotimi
- Date: 2023-10-13
- Subjects: Passerini reaction , Isocyanides , Isothiocyanate , Mechanical chemistry , Organic reaction
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/432229 , vital:72853 , DOI 10.21504/10962/432229
- Description: The global pharmaceutical industry has undergone profound transformations in the past two decades in the search for new drugs. For this reason, most pharmaceutical companies made significant investments not only in the development of new drugs but new methodologies. Modern drug development is confronted with the challenge of developing chemical reactions that are highly capable of providing most of the elements of structural complexity and diversity with the fewest possible synthetic steps for the specific target with the most intriguing properties. The discovery of more sustainable, environmentally friendly reactions capable of forming multiple bonds in a single step has been a challenge in organic synthesis over the years. Many organic chemists have recently started focusing on creative ways of reducing environmental pollution. The use of hazardous solvents has been reduced or eliminated in research to limit harm to both people and the environment. The pursuit of this goal has drawn many organic chemists to the study of various sustainable synthetic techniques including catalysis, aqueous organic reactions and mechanochemistry. The scope of this thesis was to apply sustainable techniques to design multicomponent synthetic protocols for the Passerini reaction and further apply these new protocols to construct spiro-heterocyclic compounds, all based on green chemistry principles. There is a need to develop rapid, efficient, and versatile strategies for the synthesis of bioactive molecules via multicomponent reactions. This project tried to avoid some of the pitfalls of traditional approaches, such as toxicity, low yield, long reaction times, harsh conditions, experimental complexity, and limited functionalization scope. This was achieved by focussing on the use of isonitriles and isothiocyanates as key reactive intermediates, and making extensive use of aqueous reaction conditions, mechanochemistry and microwave activation. , Thesis (PhD) -- Faculty of Science, Chemistry, 2023
- Full Text:
- Date Issued: 2023-10-13
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