- Title
- Co-crystal formation of pharmaceutical and veterinary tranquilizer molecules
- Creator
- Mngwengwe, Bongeka Naledi Precious
- ThesisAdvisor
- Smith, V.
- ThesisAdvisor
- Walker, R.B.
- Subject
- Uncatalogued
- Date
- 2024-10-11
- Type
- Academic theses
- Type
- Master's theses
- Type
- text
- Identifier
- http://hdl.handle.net/10962/464532
- Identifier
- 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.
- Description
- Thesis (MSc) -- Faculty of Science, Chemistry, 2024
- Format
- computer, online resource, application/pdf, 1 online resource (77 pages), pdf
- Publisher
- Rhodes University, Faculty of Science, Chemistry
- Language
- English
- Rights
- Mngwengwe, Bongeka Naledi Precious
- Rights
- Use of this resource is governed by the terms and conditions of the Creative Commons "Attribution-NonCommercial-ShareAlike" License (http://creativecommons.org/licenses/by-nc-sa/2.0/)
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details | SOURCE1 | MNGWENGWE-MSC-TR24-173.pdf | 5 MB | Adobe Acrobat PDF | View Details |