Browsing by Author "Caira, Mino"

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    Metal complexes of anti-tubercular drugs
    (2018) Dauda, Khadijah Tolulope; Caira, Mino; Jackson, Graham E
    There is a continuing need to improve anti-tubercular drugs due to the development of resistance towards existing drugs. In some cases, metal complexes are known to improve the bioavailability of drugs. Hence the present study looks at the use of metal complexes of anti-tubercular drugs to improve the permeability and bioavailability of the drugs. The anti-tubercular drugs isoniazid (ISO), ethambutol (EMB), para-aminosalicylic acid (PAS), rifampicin (RFN) and pyrazinecarboxamide (PZA) were used in this study. Since the solubility and hence permeability and bioavailability of the drugs depend on their solution speciation, the equilibrium constants for the reaction of H+ , Cu(II), Ni(II) and Zn(II) with the ligands were measured, in aqueous solution, at 25  0.01C and an ionic strength of 0.15 M (NaCl) using glass electrode potentiometry. The structures of the complexes with EMB, ISO and PAS were investigated using ultravioletvisible spectroscopy. The visible spectra obtained for the different species of EMB in solution were typical of Cu(II) and Ni(II) complexes. The spectra found for the various species of ISO and PAS in solution were also characteristic of their Cu(II) complexes. The results from the visible spectra support the structures postulated from the potentiometric data. This study also considered membrane permeability and absorption using a Franz cell and octanol/water partition coefficients. Partition coefficient studies showed that ISO and PZA and their complexes are hydrophilic while RFN and PAS and their complexes are lipophilic. The incorporation of a metal-ion improves the lipophilicity/hydrophilicity properties of the ligand. The presence of metal greatly enhanced the permeation of ISO through an artificial membrane in the order Cu(II) > Zn(II) > Ni(II) > ISO. A significant improvement was also found when Cu(II) was incorporated into the RFN system with an enhancement factor of 20. Zn(II) was vii able to improve the permeation of PAS with an enhancement ratio of 2. The incorporation of Cu(II), Ni(II) and Zn(II) does not affect the flux and permeability coefficient of PZA. Since the drugs are administered in tablet form, attempts were made to synthesise the metal complexes of the drugs in solid form. X-ray crystallography could then be used to confirm the solution structures. Co-precipitation, refluxing and mechanochemical methods (neat and liquid-assisted co-grinding) were employed to synthesise Cu(II), Ni(II) and Zn(II) complexes of the series of anti-tubercular drugs. However, despite exhaustive efforts, all experiments resulted in the formation of only physical mixtures of the reactants, as revealed by chromatographic and X-ray diffraction methods. This impelled the use of the solvothermal method as an alternative technique. ISO and PZA metal complexes were synthesised via this method. Unexpected products were obtained, as indicated unambiguously by single crystal Xray diffraction, and a probable mechanism for their formation was postulated. The incorporation of metals into anti-tubercular drugs has a significant influence in improving the permeability of the parent drug. It was found that the presence of Cu(II), Ni(II) and Zn(II) improved the permeability coefficient of ISO, while Cu(II) improved RFN and Zn (II) enhanced that of PAS.
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    Polymorphism and cyclodextrin inclusion complexes of antihypertensive agents
    (2006) Mhlongo, Welcome Thabani; Caira, Mino; Nassimbeni, Luigi
    The objective of the project described in this thesis was to isolate polymorphs, solvates and cyclodextrin inclusion complexes of antihypertensive agents. The physical properties of different polymorphs of a given drug are of significant interest to the pharmaceutical industry. The solubility enhancement of poorly soluble drugs by encapsulating them within cyclodextrins is also an important pharmaceutical consideration. The drugs investigated were atenolol, metoprolol, oxprenolol free bases and two salts, namely oxprenolol hydrochloride and metoprolol tartrate. No polymorphs of these antihypertensive agents were isolated but metoprolol yielded a solvate with n-hexane. Single crystals of atenolol, metoprolol, metoprolol tartrate and oxprenolol were isolated and their X-ray structures are reported here for the first time. Inclusion complexes of atenolol, metoprolol and oxprenolol free bases with cyclodextrins were successfully investigated in the solid state. The cyclodextrin hosts used for drug inclusion were P-cyclodextrin, y-cyclodextrin, heptakis(2,6-di-O-methyl)-P-cyclodextrin, heptakis(2,3,6-tri-O-methyl)-P-cyclodextrin and exakis(2,3,6-tri-O-methyl)-acyclodextrin. A new crystal form of heptakis(2,3,6-tri-0-methyl)-P-cyclodextrin as a trihydrate was isolated in an attempt to produce an inclusion complex between this host compound and the drug substance atenolol. The first crystal form of this host compound, a monohydrate, was previously discovered by the Supramolecular Chemistry Research Unit at the University of Cape Town. The various analytical techniques utilised for the characterisation of the solid-state properties of the species were elemental analysis as well as thermal, X-ray diffraction and spectroscopic techniques. Single crystal X-ray diffraction was the principal technique used for investigation of structural features. The structure of metoprolol revealed one molecule per asymmetric unit while the structure of the metoprolol solvate revealed eight molecules of metoprolol and one of n-hexane per asymmetric unit. Structure solution was successful for six cyclodextrin inclusion complexes. The oxprenolol guest molecule was successfully modelled in P-cyclodextrin and heptakis(2,3,6-tri-0-methyl)-P-cyclodextrin. Metoprolol was successfully modelled in hexakis(2,3,6-tri-O-methyl)-a-cyclodextrin but could not be modelled in heptakis(2,3,6- tri-O-methyl)-p-cyclodextrin and P-cyclodextrin due to its severe disorder. The computed powder X-ray diffraction (PXRD) patterns of the oxprenolol-˜- cyclodextrin (OXPRBCD) and atenolol-P-cyclodextrin (ATBCD) inclusion complexes were different from their experimental PXRD patterns. This indicated that phase transformation had occurred upon grinding the single crystals for each of these complexes. These two complexes crystallise in space group Pl [with unit cell parameters a˜ 18, b ˜15 and c ˜ 15 A]; thus, they are isostructural. However, their experimental PXRD patterns are different from each other. The comparison of these experimental PXRDs with published reference patterns for P-cyclodextrin complexes showed that grinding OXPRBCD transformed this material into a form crystallising in the space group P21 while grinding ATBCD resulted in its transformation to a phase belonging to the space group C2. Such transformations have not been reported previously. Among the free bases studied, atenolol is the only one that is currently commercially available as a medicinal agent. Exploitation of metoprolol and oxprenolol free bases as guests for cyclodextrin inclusion has led to the isolation and full characterisation of new inclusion complexes that have potential for further pharmaceutical development.
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    Open Access
    Polymorphism and cyclodextrin inclusion complexes of antihypertensive agents
    (2006) Mhlongo, Welcome Thabani; Caira, Mino; Nassimbeni, Luigi
    The objective of the project described in this thesis was to isolate polymorphs, solvates and cyclodextrin inclusion complexes of antihypertensive agents. The physical properties of different polymorphs of a given drug are of significant interest to the pharmaceutical industry. The solubility enhancement of poorly soluble drugs by encapsulating them within cyclodextrins is also an important pharmaceutical consideration. The drugs investigated were atenolol, metoprolol, oxprenolol free bases and two salts, namely oxprenolol hydrochloride and metoprolol tartrate. No polymorphs of these antihypertensive agents were isolated but metoprolol yielded a solvate with n-hexane. Single crystals of atenolol, metoprolol, metoprolol tartrate and oxprenolol were isolated and their X-ray structures are reported here for the first time. Inclusion complexes of atenolol, metoprolol and oxprenolol free bases with cyclodextrins were successfully investigated in the solid state. The cyclodextrin hosts used for drug inclusion were P-cyclodextrin, y-cyclodextrin, heptakis(2,6-di-O-methyl)-P-cyclodextrin, heptakis(2,3,6-tri-O-methyl)-P-cyclodextrin and exakis(2,3,6-tri-O-methyl)-acyclodextrin. A new crystal form of heptakis(2,3,6-tri-0-methyl)-P-cyclodextrin as a trihydrate was isolated in an attempt to produce an inclusion complex between this host compound and the drug substance atenolol. The first crystal form of this host compound, a monohydrate, was previously discovered by the Supramolecular Chemistry Research Unit at the University of Cape Town. The various analytical techniques utilised for the characterisation of the solid-state properties of the species were elemental analysis as well as thermal, X-ray diffraction and spectroscopic techniques. Single crystal X-ray diffraction was the principal technique used for investigation of structural features. The structure of metoprolol revealed one molecule per asymmetric unit while the structure of the metoprolol solvate revealed eight molecules of metoprolol and one of n-hexane per asymmetric unit. Structure solution was successful for six cyclodextrin inclusion complexes. The oxprenolol guest molecule was successfully modelled in P-cyclodextrin and heptakis(2,3,6-tri-0-methyl)-P-cyclodextrin. Metoprolol was successfully modelled in hexakis(2,3,6-tri-O-methyl)-a-cyclodextrin but could not be modelled in heptakis(2,3,6- tri-O-methyl)-p-cyclodextrin and P-cyclodextrin due to its severe disorder. The computed powder X-ray diffraction (PXRD) patterns of the oxprenolol-˜- cyclodextrin (OXPRBCD) and atenolol-P-cyclodextrin (ATBCD) inclusion complexes were different from their experimental PXRD patterns. This indicated that phase transformation had occurred upon grinding the single crystals for each of these complexes. These two complexes crystallise in space group Pl [with unit cell parameters a˜ 18, b ˜15 and c ˜ 15 A]; thus, they are isostructural. However, their experimental PXRD patterns are different from each other. The comparison of these experimental PXRDs with published reference patterns for P-cyclodextrin complexes showed that grinding OXPRBCD transformed this material into a form crystallising in the space group P21 while grinding ATBCD resulted in its transformation to a phase belonging to the space group C2. Such transformations have not been reported previously. Among the free bases studied, atenolol is the only one that is currently commercially available as a medicinal agent. Exploitation of metoprolol and oxprenolol free bases as guests for cyclodextrin inclusion has led to the isolation and full characterisation of new inclusion complexes that have potential for further pharmaceutical development.
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    Synthesis and characterisation of new multi-component compounds containing the non-steroidal anti-inflammatory drugs fenbufen and S(+)-ibuprofen
    (2024) Fr, sler Hannah; Caira, Mino
    Fenbufen and S-(+)-ibuprofen are non-steroidal anti-inflammatory drugs with poor aqueous solubility. In attempts to improve their solubility and bioavailability, crystal engineering techniques were employed to synthesise salts, co-crystals and cyclodextrin inclusion complexes containing these drugs. All newly discovered phases were characterised using single-crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), hot stage microscopy (HSM), Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA) and proton nuclear magnetic resonance (1H NMR) spectroscopy. The synthesis of metal salts of fenbufen containing sodium, potassium, calcium and magnesium ions was attempted. Sodium (Fen-Na+ ) and potassium (Fen-K + ) salts were successfully synthesised and characterised, the former also being successfully characterised by SCXRD. Using Fen-Na+ as a potential ‘guest', the syntheses of inclusion complexes with β-cyclodextrin (BCD) and γ-cyclodextrin (GCD) were attempted. The resulting complexes, BCD∙Fen-Na+ , and GCD∙Fen-Na+ , were successfully synthesised and characterised and were shown to have 1:1 cyclodextrin-salt compositions. Solubility studies of all salts and cyclodextrin inclusion complexes reported in this dissertation were performed in both aqueous and Fasted State Simulated Intestinal Fluid (pH 6.5) media. Phase solubility studies of fenbufen were carried out using hydroxypropyl β-cyclodextrin (HPBCD), randomly methylated β-cyclodextrin (RAMEB), γ-cyclodextrin (GCD) and sulfobutyl ether βcyclodextrin sodium (SBEBCD). RAMEB effected the greatest solubility enhancement of fenbufen by a factor of ~200 at the highest CD concentration employed. Liquid-assisted grinding (LAG) and co-precipitation experiments involving fenbufen and watersoluble coformers resulted in the successful synthesis and full characterisation of an ionic co-crystal consisting of fenbufen and isonicotinamide (FEN-ISN) with 2:3 stoichiometry. Salts of S-(+)-ibuprofen with the antifibrinolytic agents 6-aminocaproic acid [(S-IBU)- (ACA)+ ] and tranexamic acid [(S-IBU)- (TXA)+ ] were successfully synthesised and comprehensively characterised. A second crystalline form of a cyclodextrin inclusion complex between S-IBU and heptakis(2,6-diO-methyl)-β-cyclodextrin (DMB∙S-IBU) was discovered. All new phases, (S-IBU)- (ACA)+ , (S-IBU)- (TXA)+ and DMB∙S-IBU, were found to occur with 1:1 stoichiometry.
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    Synthesis and inclusion of S-aryl alkylthiosulfinates as stable allicin mimics
    (2007) Stellenboom, Nashia; Hunter, Roger; Caira, Mino; Bourne, Susan; Cele, Khethiwe; Qwebani, Tozama
    S-Aryl alkylthiosulfinates showing aromatic rings with varying electronic demand have been prepared by oxidation of the corresponding disulfide, the latter prepared using new one-pot methodology involving thiol oxidation with 1-chlorobenzotriazole. Whereas thiosulfinates with electron-withdrawing substituents in the aromatic ring were unstable towards isolation, those with a releasing substituent in the para-position have shown good stability as potential allicin mimics and one of them (p-OMe) has been characterised as its inclusion compound in the cyclodextrin, TRIMEB, by X-ray crystallography.