The crystal engineering of two antibacterial pharmaceutical ingredients: cocrystals and molecular salts of a series of sulfa-drugs and the polymorphism and cocrystals of an isoniazid derivative
| dc.contributor.author | Scheepers, Matthew Clarke | |
| dc.date.accessioned | 2024-02-06T09:20:21Z | |
| dc.date.available | 2024-02-06T09:20:21Z | |
| dc.date.issued | 2024 | |
| dc.description | A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Faculty of Science, School of Chemistry, University of the Witwatersrand, Johannesburg, 2023 | |
| dc.description.abstract | Crystal engineering is the design and synthesis of new solid forms by using the knowledge of intermolecular interactions and crystal packing. The goal of crystal engineering is to improve the properties of materials without altering the chemical identity of the materials. This work can be divided into three major parts. The first part deals with a series of sulfa drugs and its cocrystals. The second part deals with exploring the cocrystals of 3,5-dinitrobenzoic acid, in particular using Hirshfeld surfaces. The last part deals with the polymorphism of an isoniazid derivative and the cocrystals formed with it. In all cases these new solids were characterized by single crystal X-ray diffraction (SC-XRD), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), and Fourier-transform infrared spectroscopy (FTIR). When designing new solid forms (cocrystals and molecular salts) it would be ideal to use a knowledge based system on the use of synthons. Sometimes this knowledge is limited and can hinder future work. Sulfa drugs such as sulfamethazine (sz), sulfapyridine (sp), sulfathiazole (st) and sulfamethoxazole (sm) have been shown to exhibit unique solid-state behaviour such as cocrystal-salt polymorphism and tautomerism. The number of known cocrystals and molecular salts consisting of the mentioned drugs are limited, which hinders research into exploring this interesting solid-state behaviour. Therefore, the structural landscape of these sulfa drugs was expanded in hopes of observing new cases where this solid-state behaviour is observed. Cocrystals and molecular salts of these sulfa drugs were synthesized using various techniques, such as solvent evaporation and mechanochemical grinding (both dry and liquidassisted grinding). Twenty-five different coformers were chosen to use for these cocrystallization experiments, most of which are either benzoic acid/benzoic acid derivatives or a pyridine derivative. sz formed eight successful cocrystals and one molecular salt with benzoic acid and its derivatives. SC-XRD showed that eight of the coformers that interacted iii with sz formed the sulfonamide-carboxyl synthon; the only exception to this was sz + 4- hydroxybenzoic acid, which the sulfonimide-carboxyl synthon formed instead. Five cocrystals and one molecular salt containing st, three cocrystals and one molecular salt of sm, and four cocrystals and one molecular salt containing sp were also synthesized. Most of these included using 2-aminopyridine or one of its derivatives. The second part deals with the cocrystals and molecular salts of 3,5-dinitrobenzoic acid (dnba). dnba is often used as a popular coformer for crystal engineering purpose. However, very little work centered on dnba with coformers has been reported. In this work we report new multicomponent crystals containing dnba, which include one hydrate, one solvate, one molecular salt, and four cocrystals. The coformers include: 2-acetylpyridine, 3-cyanopyridine, flufenamic acid, 4-dimethylaminobenzophenone, pyridoxine, theophylline, and thiourea. In addition to the strong hydrogen bonding expected, several weaker intermolecular interactions were identified using Hirshfeld surfaces, which included C−H···π bonding, π-hole, and π···π interactions. The Hirshfeld surfaces indicated that these weaker interactions had a significant effect on the packing of these multi-component crystals. These multi-component crystals were compared with the crystal structures reported in the Cambridge structural database (CSD), which has given some significant insights in the structural landscape of dnba. Isoniazid (inh) is a simple, useful active pharmaceutical ingredient (API) used to treat Myobacterium tuberculosis. It is composed of a hydrazine and pyridine ring. The hydrazine group can be modified in a multitude of ways, including using a Schiff-base condensation reaction. This is achieved by using an appropriate ketone or aldehyde. In this work isoniazid was derivitised using diacetone alcohol (4-hydroxy-4-methyl-2-pentanone), generating N’- [(2E)-4-hydroxy-4-methylpentan-2-ylidene]pyridine-4-carbohydrazide (iz4h4m2p). This derivative was found to be polymorphic, existing in two forms, form I and form II. The iv difference between these two forms is distinguished by the major hydrogen bond pattern, which is either a chain hydrogen bond motif formed between the hydroxyl group and amide groups (the pyridine ring is not involved) or a ring based hydrogen bond motif that forms dimers with the hydroxyl group forming a hydrogen bond to the pyridine ring. Form I was found to be metastable with respect to form II, with form I converting to form II upon heating before melting. Form II does not convert to form I. In addition to exploring the polymorphism of iz4h4m2p, several cocrystals of iz4h4m2p were synthesized. The coformers chosen were benzoic acid derivatives. Most of these cocrystals formed a hydrogen bond between the carboxylic acid and pyridine ring. This left the hydroxyl group of iz4h4m2p to form a hydrogen bond to the amide group, forming a chain hydrogen bond motif similar to the one observed in form I. The only deviation from this was observed in cocrystals where the benzoic acid included a hydroxyl group of its own, such as 2,5-dihydroxybenzoic acid. | |
| dc.description.librarian | TL (2024) | |
| dc.faculty | Faculty of Science | |
| dc.identifier.uri | https://hdl.handle.net/10539/37521 | |
| dc.language.iso | en | |
| dc.phd.title | PhD | |
| dc.school | Chemistry | |
| dc.title | The crystal engineering of two antibacterial pharmaceutical ingredients: cocrystals and molecular salts of a series of sulfa-drugs and the polymorphism and cocrystals of an isoniazid derivative | |
| dc.type | Thesis |
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