The work summarizes the results of a studies conducted with six different flushing agents, i.e. two anionic surfactants (SDS and DOWFAX 8390), two complexing agents (cyclodextrins), a humid acid, and an alcohol (ethanol), for solubilizing and removing residual-phase immiscible liquid from porous media. Batch experiments were conducted to measure the degree of trichloroethene (TCE) and tetrachloroethene (PCE) solubilization induced by these agents. These studies revealed that the solubility of TCE and PCE was enhanced significantly. Column experiments were conducted to compare water and agent-enhanced flushing of Borden sand containing residual saturations of TCE and PCE. The results of these studies indicate that the total flushing volume necessary to remove the contaminant was reduced substantially in the presence of all applied agents. The relative effectiveness of the agents varied based on the method of evaluation. It was shown that a volatile contaminant, e.g. toluene, TCE, and PCE, can be separated from cyclodextrin solution by mean of air-sparging. The cyclodextrin solution was successfully reused for continuos flushing of a contaminated porous material. The simulation of selected experiments revealed that the mass transfer rate coefficients are generally increasing if evaluated based on the aqueous driving force approach. However, a relation based on the enhanced driving force approach was found to be less significant. Even though areas of additional research have been identified, this research contributes to a better understanding of the processes governing chemically enhance flushing of contaminated porous media.

Although iron occurs at extremely low concentrations in the world’s oceans, it is essential for all living organisms. It is the limiting nutrient in High Nutrient Low Chlorophyll (HNLC) areas of the ocean, and exerts critically important influences on levels of atmospheric CO2 and the global carbon cycle. Understanding the chemical processes that govern the fluxes and biogeochemistry of oceanic iron requires thorough assessment of the aqueous physical chemistry of iron and analytical techniques capable of measuring iron at sub-nanomolar concentration measurements. This dissertation extends prior work on the physical and analytical chemistry of iron through (a) investigation of the complexation of iron by silicate in aqueous solutions, (b) investigation the solubility of ferric hydroxide using spectrophotometric procedures over a wide range of pH (c) utilization of novel in-situ instrumentation for iron measurements in seawater. Previous investigations of ferric iron complexation by silicate ions (SiO(OH)-3) included no measurements at ionic strengths greater than 0.15 molal and produced formation constant estimates at zero ionic strength that differed by more than a factor of two. In this work ferric silicate formation constants were measured at ionic strengths of 0.1, 0.3 and 0.7 molal by ultraviolet absorbance spectroscopy. The dependence of the ferric silicate formation constant on ionic strength at 25° C, summarized using the Bronsted-Guggenheim-Scatchard specific ion interaction (SIT) model, indicated that the ionic strength dependence of the ferric silicate formation constant, (written as Si ∗β1 = [FeSiO(OH)23+][H+][Fe3+]-1[Si(OH)04]-1) can be expressed as: log Si *β1 = (-0.125 ± 0.042) - (2.036 I0.5)/(1+ 1.5I0.5) + (0.588 ± 0.094) I. The result obtained at zero ionic strength is in good agreement with the average result obtained in four previous studies, but with a substantially reduced level of uncertainty. The solubility of ferric iron in aqueous sodium perchlorate solutions at the ionic strength of seawater was determined by use of novel automated spectrophotometric procedures. Two colorimetric measurement chemistries were utilized to measure dissolved ferric iron concentrations in equilibrium with precipitated amorphous ferric hydroxide over a range of pH between 4.0 and 12.0. Soluble iron concentrations decreased from approximately 3.2 micromolar at pH 4.0 to subnanomolar levels between pH 7.5 and 9.5, and rose to approximately 0.1 micromolar at pH 12. The results of this investigation were in good agreement with solubility results obtained in previous investigations of iron solubility in seawater at circumneutral pH, and previous results obtained in sodium chloride at high pH, but differed from previous results obtained in sodium chloride between pH 7 and pH 9. In view of the agreement between solubility results obtained in seawater and sodium perchlorate (this work) and, in contrast, results in sodium chloride that were more than an order of magnitude lower than were obtained in seawater and sodium perchlorate, it is advisable that further solubility investigations are performed in sodium chloride solutions. The iron measurement procedures developed for the investigation of ferric iron solubility were incorporated in an in situ spectrophotometric instrument. The Spectrophometric Elemental Analysis System (SEAS) utilizes long pathlength absorbance spectrometry (LPAS) combined with colorimetric protocols to achieve the sensitivity required to measure analytes at nanomolar concentration levels. The M-SEAS was initially tested on cruises in the Eastern Gulf of Mexico in June 2013 and November 2013. Due to limited opportunity for deployments of M-SEAS during these cruises, iron concentration data was obtained from only three casts. During these casts the heater pressure vessel flooded due to a compromised seal, causing the temperature of both channels to be strongly affected by ambient seawater. Further measurements of iron with the M-SEAS instrument in profiling mode will require an engineering analysis and redesign of the faulty seal. The international GEOTRACES program has stated that an improved understanding of the biogeochemical cycles and largescale distributions of trace-elements and isotopes will inform many areas of environmental research, from climate science to planning for future global change. As the only instrument currently capable of continuous in situ measurements of iron, the M-SEAS instrument should greatly enhance capabilities for investigation of iron biogeochemistry.

The UPPER (Unified Physicochemical Property Estimation Relationships) model uses additive and non-additive parameters to estimate 21 biologically and environmentally important physicochemical properties of organic compounds. Thermodynamically sound relationships are used to predict boiling and melting points, aqueous and octanol solubilities, vapor pressure and the air-octanol, air-water and octanol-water partition coefficients. These properties determine the distribution and fate of organic compounds in biological and environmental systems. The model has been validated on a data set of 2000 hydrocarbons and polyhalogenated hydrocarbons, provides a simple and accurate method to predict the properties studied.

Preformulation studies of two naturally occurring compounds, sulforaphane and myricetin, are presented. Both compounds have shown promise as chemoprevention agents throughout the literature. Despite this evidence, minimal information is available to guide the progression of formulations designed for future drug development. The presented work describes solubility, stability, and solid-state characterization of these compounds. Additionally, a mathematical model based on the ideal solubility equation, which reasonably estimates the solubility of a hydrate is described. This model accounts for the dehydration energetics of the solute as it transforms from hydrate to anhydrous prior to melting and conversion to a hypothetical super-cooled liquid (HSL). This model will lend itself to the appreciation of the solubility differences that can exist between hydrate and anhydrous drug forms. By improving the accuracy of solubility estimation, drug development studies involving hydrates can be designed more accurately.

No description available.

Administering drug therapy through the intravenous route ensures rapid, and complete, bioavailability, which can be critical in an emergency situation. However, bypassing all of its protective barriers leaves the body vulnerable to harm if the parenteral formulation becomes unstable when mixed with the blood. An example of this formulation instability is the precipitation of poorly water-soluble drugs after mixing with the blood's aqueous environment. This happens when parenteral formulations rely too heavily upon the solution pH, and excipients, to increase the drug solubility. This precipitation in the blood can damage venous cell membranes producing symptoms ranging from mild skin irritation to death. To screen potential drug formulations for problems such as injection site drug precipitation, pharmaceutical companies have traditionally used costly and time consuming animal studies. To reduce the amount of pre-clinical animal studies necessary to find an optimal IV formulation, an in vitro device to detect injection site drug precipitation is introduced. In addition to the device, software that simulates the dilution of a parenteral drug formulation with blood upon administration has been developed and is introduced. Both the device and software were tested on commercially available formulations plus one formulation currently in clinical trials. The results and capabilities of the new device were compared to those obtained using an earlier in vitro device. Finally, a robust model for early screening of injection site precipitation is developed using both the in vitro device and software.

No description available.

No description available.

In most cases, organic materials exist in the solid phase as polymorphs, solvatomorphs or amorphous forms. Physico-chemical properties in the solid-state are all affected primarily in terms of dissolution, solubility, bioavailability, stability and processability. Therefore investigation into the polymorphic behaviour of APIs has become a mandatory part of drug characterisation studies by pharmaceutical companies (Giron, 2001). The influence polymorphism has on bioavailability and the need for the development of drugs in the amorphous form have instigated regulatory bodies such as the FDA to require solid-state characterisation of pharmaceuticals (Strachan et al., 2005). Subsequently a study was conducted to determine the physico-chemical properties of two poorly watersoluble macrolides; clarithromycin and spiramycin. Characterisation methods included: XRPD, IR, TGA, DSC, SEM, Karl Fischer titration, solubility and stability studies. Recrystallisations of spiramycin from various solvents indicated that this API mainly exists in the amorphous form. The DSC proved to be of little value in the characterisation of this particular macromolecular antibiotic, since wide inter-sample variations were mostly obtained. TGA results showed higher solvent uptake than expected. This was ascribed to the amorphous, sponge-like character of this drug. For the sake of reproducibility and quality of the results, characterisation of spiramycin was more reliant on spectroscopic and crystallographic methods. Samples generated from 2- butanol, chloroform, ethyl acetate, 1.4-dioxane, methanol, n-propanol, iso-propanol and tetrahydrofuran showed characteristic peaks in the range of 2000-2400 cm-1 that were not present in the IR spectrum of the raw material. Conversely, the XRPD patterns were all identical, exhibiting a characteristic “halo” pattern with no detectable Bragg diffraction peaks. A solubility assessment showed no significant differences between the raw material and the recrystallisation products. In fact the raw material seemed to be the form with the highest solubility, albeit it only by a small margin. According to the literature, clarithromycin exists in five forms. Form 0 exists as a solvate, form I is a metastable form, form II is the stable form (Liu & Riley 1998; Deshpande et al., 2006), form III is a solvate of acetonitrile (Liu et al., 2003; Liang & Yao, 2008) and form IV is a hydrate (Avrutov et al., 2003). The stable form II is used in formulations currently on the market. A follow-up study was done relating to a study performed by De Jager (2005). The raw material (form II) was recrystallised from acetonitrile, chloroform and ethyl acetate. Two new crystal forms were prepared from chloroform and acetonitrile. With the necessary driving force, both of these crystals forms are able to convert to the thermodynamically stable form II. In addition, a solvate recrystallised from chloroform together with its corresponding desolvate, showed a 4 and 1.5 fold respective increase in solubility when compared to the raw material. The recrystallisations from ethyl acetate delivered crystals with an XRPD pattern similar to form II. This proved that clarithromycin can be recrystallised directly from this solvent without the need of an additional conversion step, as was the case in the study done by De Jager (2005). / MSc (Pharmaceutics), North-West University, Potchefstroom Campus, 2013

Roxithromycin is a semi-synthetic, macrolide antibiotic, derived from erythromycin A. It acts as a bacteriostatic drug at low concentrations and a bactericidal drug at high concentrations. It binds to the 50S subunit of the 70S ribosome, which causes the reversible inhibition of RNA-dependent bacterial protein synthesis. It is well known that active pharmaceutical ingredients (APIs) may exist in numerous solid states. Differences in the solid state significantly influence the physical and chemical properties of an API. The in vivo performance of a dosage form will also be influenced by the solid state properties of a given pharmaceutical active. The amorphous characteristics of APIs have a significant impact on their performance and thus offer the potential for exciting new pharmaceuticals. Whilst amorphous forms of poorly soluble APIs are more soluble than their crystalline counterparts, they tend to be physically unstable, which makes their formulation into solid dosage forms quite challenging. Roxithromycin has only 50% oral bioavailability due to its poor aqueous solubility and for this reason, its potential for optimal therapeutic effect are limited. Poor solubility is thus an important obstacle in formulation development. During this study, amorphous forms of roxithromycin were prepared via quench cooling, and desolvation of chloroform- and ethyl acetate solvates. These amorphous forms were characterised by means of several techniques, whilst their solubilities and stabilities were also investigated. The outcomes of the solubility studies illustrated the complexity of this API and its amorphous forms with regards to their interactions with water. Solubility studies confirmed the superior solubility of the roxithromycin glass (prepared through quench cooling) and amorphous forms (desolvation of solvates) over the roxithromycin monohydrate in water. The solubility in water improved in the order of roxithromycin monohydrate < roxithromycin glass < roxithromycin glass powder < amorphous chloroform desolvate. The roxithromycin monohydrate, as well as the amorphous forms of roxithromycin demonstrated stability over a one-month period of exposure 40°C and relative humidity (RH) of 75%. The roxithromycin glass powder tended to revert to the more stable crystalline monohydrate after week 3 of stability testing. The roxithromycin glass at lower temperatures of 25°C and 30°C (both at 75% RH) tended to transform into the more crystalline form at week 4 of the study. These transformations were, however, not as significant as during the 40°C / 75% RH study. The conclusion could therefore be made that this transformation into the crystalline form was more temperature – than moisture dependant. At a higher temperature (at identical humidity conditions), the transformation into the crystalline form was much faster. Stability studies on the two roxithromycin desolvates were also performed in order to determine whether these amorphous forms, would differ, with regards to their stability, from the glass prepared through heating and cooling. It was determined that the desolvates were more stable than the roxithromycin glass. / Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2012