Azithromycin, an azalide and member of the macrolide group, is a broad spectrum antimicrobial, representing one of the bestselling antimicrobials worldwide. It is derived from erythromycin and exhibits improved acidic stability as a result of its structural modifications. The stable solid form of azithromycin is its dihydrate, although it also naturally occurs in its metastable forms, i.e. the monohydrate and anhydrate. Because azithromycin is poorly soluble in water, its absorption from the gastro-intestinal tract is negatively influenced, which ultimately affects its bioavailability following oral administration (37 %). Polymorphic (monohydrates and dihydrates) and anhydrous forms of azithromycin were screened and investigated. One anhydrous form also proved to be amorphous, which shifted the focus of this study from polymorphism to amorphism. An amorphous glassy azithromycin was subsequently prepared and fully characterised to present its solid state profile. The stability of this amorphous glassy form was established at a high temperature and relative humidity over a period of four weeks. Exposure to increased relative humidity (up to 95 %) and increased water content (up to 50 %) also served as stability indicating tests. Its solubility in various aqueous media was determined. A solid dosage form (tablet), containing the azithromycin glass, was prepared, whereafter these tablets were subjected to dissolution studies in different aqueous media. The stability of azithromycin glass in tablet form was determined over a period of three months. The permeability of azithromycin glass across excised pig intestinal tissue was further established at various pH values. This amorphous glassy form of azithromycin (AZM-G) proved to be very stable at high temperature and relative humidity, whilst also remaining stable after prolonged exposure to 95 % of relative humidity, as it only adsorbed moisture onto its surface. Water content (up to 50 %) had no plasticising effect on azithromycin glass. It demonstrated a significantly higher water solubility (339 % improvement) in comparison with the commercially available azithromycin dihydrate and was it also 39 % more soluble in phosphate buffer (pH 6.8) than its dihydrate counterpart. The prepared azithromycin glass tablets showed a promising dissolution profile in water, due to the improved water solubility of this glass form. The transport of azithromycin glass at higher pH values (6.8 and 7.2) across the membrane proved to be significantly higher than that of azithromycin dihydrate, thus also illustrating its pH dependence for its transport across pig intestinal tissue. The improved water solubility of the azithromycin glass, together with its faster dissolution rate, its superior stability and its increased permeability, may ultimately result in a higher azithromycin bioavailability following oral administration. These research outcomes hence give rise to the need for investigating the effect of administering lower dosages of azithromycin and to determine whether the same antimicrobial efficacy would possibly be achieved, due to maintaining the same tissue concentration levels at these lower dosages. / Thesis (PhD (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013

Due to the immuncompromised status of AIDS patients, secondary infections and malignancies are common. Conditions secondary to AIDS for which patients require treatment include Karposi's sarcoma (treated with methotrexate), varicella-zoster (treated with antivirals such as acyclovir) and herpes simplex (also treated with antivirals like acyclovir or idoxuridme). However the clinical efficacy of these drugs is limited by poor skin permeability. Few reports, however, have dealt with the delivery of low molecular weight hydrophilic drugs from these vesicles (El Maghraby et al, 2000). The aim of our study was to investigate in vitro permeation of methotrexate, acyclovir and idoxuridine across human epidermal membrane from elastic liposomes. The intent was to establish whether formulation of these hydrophilic drugs into elastic liposomes would enhance their skin permeation parameters. We developed and validated high-performance liquid chromatographic techniques for quantitative analysis of methotrexate, idoxuridine and acyclovir. Elastic liposomes were prepared from various phospholipids- phosphatidylcholine 78.6%; phosphatidylcholine 50%; hydrogenated phosphatidylcholine 90%; phosphatidylcholine 95% and surfactants - sodium cholate, sodium deoxycholate, Span 20, 40, 60, 80. These vesicles were characterised by transmission electron microscopy. The solubilities of methotrexate, acyclovir and idoxuridine were determined. Phospholipon G (95% phosphatidylcholine) was chosen for the preparation of the liposomes with different surfactants. Permeation of methotrexate, acyclovir and idoxuridme from these vesicles across human epidermal membrane was investigated. Flux values for methotrexate, acyclovir and idoxuridine values (J) obtained by curve-fitting of data using Easyplot were compared to those obtained by linear regression. We used Student's t-test to determine statistically significant differences in the flux values of the formulations. A computer program http://www.physics.csbsju.edu/stats/ttest- bulk-form.html was used for this purpose. Our results indicate that there are no statistically significant differences between flux values from elastic liposomes and saturated aqueous solutions. / Thesis (Ph.D. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2004.

Low phosphate fertilizer efficiency in high pH soils is primarily due to the retardation of P movement in the soil-P fertilizer reaction zone. The objective of this study was to obtain fundamental information on the influence of multi-ionic interactions on the solubility and diffusion of P in columns containing a model soil system and two soil types. The study also aimed to identify the salt combinations and factors that have the potential to enhance the solubility and movement of P in calcareous soil condition. The results showed that the interaction of NH4+ and SO42- was consistent at enhancing the water solubility and movement of P under a high soil pH condition. This effect was attributed to the combination of various mechanistic factors associated with (NH4)2SO4 compound including significant pH reduction, cation exchange reaction of NH4+ with the exchangeable Ca2+, and anionic competition of SO42- with P for precipitation with Ca2+.

Experiments to measure (i) the reactivity of lithium peroxide and lithium oxide in ambient air as a function of relative humidity and reactant particle size, (ii) the solubility of lithium hydroxide and lithium hydroxide monohydrate in three alcohols, namely methanol, ethanol and 1 and 2-propanol, as a function of time and temperature, (iii) the efficiency of the production of lithium peroxide in alcohol medium as a function of the concentration of LiOH.H 2O in methanol, the concentration of hydrogen peroxide, the kind of alcohol, the kind of feed material, and temperature and the time of mixing, (iv) the analysis of the precipitates, (v) the temperature of the precipitate decomposition in isothermal and non-isothermal conditions in ambient and neutral conditions as function of time, (vi) the activation energy of the precipitate decomposition, (vii) the temperature of the lithium peroxide decomposition in isothermal and non-isothermal conditions as function of time and (viii) the activation energy of lithium peroxide decomposition were performed. / The purpose of the study was to gather the data necessary to evaluate the production of lithium peroxide, Li2O2, and subsequently lithium oxide, Li2O, to be used as a feed for a silicothermic reduction process for the production of metallic lithium. The proposed basis for the production of Li2O2 was the conversion of lithium hydroxide or lithium hydroxide monohydrate by hydrogen peroxide in an alcohol medium. Alcohols were chosen because they are members of a class of non-aqueous solvents that can selectively dissolve the anticipated contaminants while precipitating the desired products. / It was found that the addition of hydrogen peroxide to alcohol solutions containing lithium hydroxide monohydrate resulted in the formation of lithium peroxide as lithium hydroperoxidate trihydrate with eight adduct molecules of methanol, i.e., Li2O2•H2O 2•3H2O•8CH3OH and involved the peroxide group transfer. The optimum conditions for the production of lithium peroxide were found to be (i) the least water concentration in the system (ii) the use of the temperature lower than ambient temperature and (iii) fast separation of the precipitate and raffinate to prevent dissociation of the precipitate or dissolving into the raffinate. / The high solubility of LiOH.H2O and at the same time the low solubility of Li2CO3 and of Li2O2 in methanol resulted in selection of methanol as the best alcohol of those studied for the proposed method of Li2O2 production. It also yielded high purity lithium peroxide. The production of Li2O 2 using H2O2 (35 %wt) required an excess of hydrogen peroxide equal to 2.6 times the stoichiometric amount. / The thermal decomposition of the lithium hydroperoxidate trihydrate precipitate started with the rejection of the adduct methanol molecules, followed by co-evolution of H2O and H2O2 from the resulting Li 2O2•H2O2•H2O. The activation energy of the decomposition reaction of the precipitate was measured as 141 kJ/mol. At temperatures greater than 200°C, lithium peroxide was found to be very reactive with atmospheric air. However, in an argon atmosphere, it rapidly decomposed losing the majority of the oxygen atoms, followed by the gradual slow diffusion of oxygen gas absorbed on the lithium oxide.

Low phosphate fertilizer efficiency in high pH soils is primarily due to the retardation of P movement in the soil-P fertilizer reaction zone. The objective of this study was to obtain fundamental information on the influence of multi-ionic interactions on the solubility and diffusion of P in columns containing a model soil system and two soil types. The study also aimed to identify the salt combinations and factors that have the potential to enhance the solubility and movement of P in calcareous soil condition. The results showed that the interaction of NH4+ and SO42- was consistent at enhancing the water solubility and movement of P under a high soil pH condition. This effect was attributed to the combination of various mechanistic factors associated with (NH4)2SO4 compound including significant pH reduction, cation exchange reaction of NH4+ with the exchangeable Ca2+, and anionic competition of SO42- with P for precipitation with Ca2+.

The solubility parameters for ten fractions of Athabasca vacuum residue were calculated from molecular representations via group additivity methods. Two methods were used; Marrero-Gani and Fedors. The calculated parameters were compared between the fractions for consistency, and also compared with other literature sources. The results from the Marrero-Gani method were satisfactory in that the values were in the expected range and the results were consistent from fraction to fraction. The final stage of the work on group additivities was to estimate the solubility parameter values at the extraction temperature of 473 K, and then compare the solutes to the solvents. The solubility parameters of the solvents were calculated from correlations and from the molecular dynamic simulation; the latter method did not result in fulfilling values. The most reasonable solvent and solute solubility parameters were used to assess the utility of the solubility models to explain the trends. The solubility models were not suitable for these types of materials. Stability of heavy oil fractions undergoing mild thermal reactions were predicted computationally for limited sample cracked molecules.

Purpose: The aim of this study was to investigate the usefulness of formulation approaches to minimise injection site reactions for poorly soluble drugs. The specific objectives were to modify the injection site reactions by identification of irritant components in the formulation and control of their release kinetics; and to gain understanding of formulation approaches to create a favourable microenvironment in the tissues allowing better tissue tolerance and drug absorption. Methods: Physicochemical properties of the model drug, ricobendazole (RBZ) were characterised using conventional methods. Three formulation approaches to minimise irritancy of the low pH RBZ solution were assessed. An in vitro method using 96-well microplates and a microtiter plate reader was used for detection of drug precipitation on dilution for formulation characterisation. Cellular damage by the formulations was investigated in L929 fibroblasts using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy phenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) and lactate dehydrogenase (LDH) assays. Tissue tolerance and pharmacokinetics were simultaneously investigated after subcutaneous injection in sheep. A low pH RBZ solution was used as a reference formulation. Results: Preformulation studies showed that RBZ was practically insoluble in water and oils, and was slightly soluble in commonly used co-solvents. Solubility was slightly improved by complexation with hydroxypropyl-β-cyclodextrin (HP-β-CD, K₁:₁ = 311 M⁻�) or a combination of low pH (> 2) with surfactants or co-solvents. A U-shaped pH-solubility profile in aqueous solutions indicated that RBZ is an ampholyte. pKa values measured by absorbance spectroscopy and pH solubility methods were 3.45 and 3.76 (basic) and 9.82 and 9.53 (acidic) respectively. The partition coefficient was 14.3 - 15.2 at pH 6 - 9 and less at higher or lower pH. In aqueous solutions, RBZ showed a V-shaped pH-degradation rate profile and was most stable at pH 4.8. Degradation pathways were identified as hydrolysis and oxidation. Three RBZ injectables (5%) were obtained by modification of the low pH RBZ solution; addition of 20% HP-β-CD, incorporation into a w/o emulsion, and a microemulsion (ME). On dilution with SPB, the onset time of drug precipitation was prolonged and the rate was reduced in the presence of HP-β-CD. The w/o emulsion had a low viscosity (< 60 mPa.s) and exhibited Newtonian flow. Drug release versus the square root of time was linear and the release rate could be adjusted by phase ratio and droplet size. Drug release was found to be by diffusion. A coarse emulsion layer appeared at the interface between the ME and buffer. Drug release from the ME was faster than from the emulsion and was linear with the square root of time. On titration into SPB, the three formulations showed controlling effects on the release of H₃O⁺ compared to the reference formulation. RBZ (0.1 mg/ml) was more toxic to L929 cells than the co-solvent propylene glycol (50 mg/ml). The formulations showed greater cytotoxicity than their vehicles in the order: ME > RBZ solution = emulsion > HP-β-CD. HP-β-CD and emulsion excipients showed little or no cytotoxicity. The MEs exhibited more toxicity in the LDH assay than in the MTS assay. A reversed phase HPLC assay for simultaneous determination of RBZ and its metabolite in sheep plasma using an isocratic system with UV detection was developed and used in the pharmacokinetic studies. Plasma samples were prepared by solid phase extraction. A suitable internal standard was selected by quantitative structure-retention relationships analysis. The composition of a ternary mobile phase was optimised with the assistance of multiple linear regression. The assays were linear over the concentration range 10 - 1000 ng/ml for both analytes (r > 0.999) with satisfactory inter-day and intra-day precision and accuracy (CV < 10%). The recoveries for all analytes were > 96%. A pilot study in sheep suggests that injection of the vehicles (the CD, emulsion and ME) caused virtually no pain on injection or site reactions. Both the reference formulation and its vehicle induced pain on injection and resulted in swollen tissues. Histology after two weeks showed granulation for the formulation, but not the vehicle. In contrast, animals showed virtually no injection site reactions with the ME and emulsion. The HP-β-CD formulation gave transient pain on injection but a two-fold increase in bioavailability compared with the reference. The emulsion produced sustained drug release and increased drug absorption. In the main study, the HP-β-CD vehicle showed good tissue compatibility. Irritation by the HP-β-CD formulation was attributed to the low pH. Cmax, tmax and AUC0-[infinity] for the reference formulation were 1.3 � 0.3 [mu]g/ml, 9.6 � 2.9 h and 36.7 � 9.2 [mu]g�h/ml respectively, while the corresponding data for the HP-β-CD formulation were 2.9 � 0.8 [mu]g/ml, 5.0 � 0.6 h and 54.5 � 15.3 [mu]g�h/ml respectively. The half-life following the injection of the HP-β-CD formulation (5.5 � 2.8 h) was shorter than that of the reference formulation (8.5 � 3.4 h). Conclusions: Injection site reactions may be minimised by identification of irritant components in a formulation and by controlling their release. Controlling the burst release of the poorly water soluble drug RBZ in a low pH solution could improve tissue tolerance and minimise post-injection precipitation, and hence increase drug bioavailability. In addition, HP-β-CD was a useful local injectable carrier which significantly enhanced the absorption of RBZ after subcutaneous injection in sheep.

Thesis (Ph. D.)--University of Michigan, 1926.

Thesis (Ph. D.)--University of Michigan, 1926.

Thesis (Ph. D.)--Florida State University, 2006. / Advisor: Alan G. Marshall, Florida State University, College of Arts and Sciences, Dept. of Chemistry and Biochemistry. Title and description from dissertation home page (viewed Sept. 21, 2006). Document formatted into pages; contains xxii, 198 pages. Includes bibliographical references.