Acne affects as many as 80% of young adults and adolescents all over the world. This detrimental condition can be classified into four stages: (a) open comedo (blackhead), (b) closed comedo (whitehead), (c) papule and (d) pustule (Russell, 2000:357-366). There are various factors that can lead to acne outbreaks which include: (a) hormone level changes during the menstrual cycle in women, (b) certain drugs (i.e. lithium), (c) certain cosmetics and (d) environmental conditions such as humidity (University of Maryland, 2009:1). The skin performs a variety of functions which include the two major functions: (a) the containment and (b) the protection of the internal organs of the body. The containment function relates specifically to the ability of the skin to confine the underlying tissues and restrain their movement from place to place. The protective function, on the other hand, relates to the ability of the skin to act as a microbiological barrier to most micro-organisms; a chemical barrier to exogenous chemical compounds; barrier to radiation and electrical shock; and mechanical barrier to impact (Danckwerts, 1991:315). Niacinamide and salicylic acid were chosen in combination, due to the beneficial effects that they have on acne. Niacinamide has an anti-inflammatory action on acne; which reduces redness, dryness and irritation caused by Propioni-bacterium acnes that live in the clogged pores of pimples (Acnetreatmentlab, 2008:1). Salicylic acid is a keratolytic and keratoplastic agent. It is used in combination with other ingredients to enhance the shedding of corneocytes. This causes penetration into the skin to be very difficult (SAMF, 2005:177). The solubility of niacinamide and salicylic acid in PBS (pH 7.4 at 32°C) were 212.95 mg/ml and 4.07 mg/ml, respectively. The log D values of niacinamide and salicylic acid were determined to be -0.32 and 0.33, respectively. According to the solubility of niacinamide and salicylic acid it was expected that both of the active ingredients would permeate through the skin. However, it is expected that niacinamide will depict enhanced permeation with respect to salicylic acid. The results of the log D for both of the active ingredients indicate that there would not be optimal permeation. This study involved the formulation of four different acne preparations (Pheroid™cream, Pheroid™gel, cream and gel), combining niacinamide and salicylic acid. The evaluation of stability parameters for the different formulations indicated that none of the formulations was stable under the different storage conditions determined by the Medicines Control Council. Nevertheless, the cream and gel were the most stable of the four formulations. Visual assessment of the Pheroid™ formulations with the confocal laser scanning microscopy (CLMS) was conducted and inconclusive evidence to whether the active substances were entrapped within the Pheroids™, was obtained. Franz cell diffusion studies indicated that the cream (in the case of niacinamide) and gel (in the case of salicylic acid) depicted the highest average and median flux from hours 6 to 12. Results of the tape stripping studies showed that with the gel formulation, concentrations of 2.060 ug/ml and 44.749 ug/ml niacinamide were obtained in the epidermis and dermis respectively. After the Pheroid™ gel was applied, tape stripping depicted only 1.587 ug/ml niacinamide in the epidermis with respect to 22.764 ug/ml niacinamide in the dermis. The cream formulation, on the other hand, showed niacinamide concentrations of 2.001 ug/ml in the epidermis and 13.363 ug/ml in the dermis, whereas with the Pheroid™ cream formulation, concentrations of 1.097 ug/ml and 18.061 ug/ml were obtained in the epidermis and dermis respectively. Tape stripping results depicted that with the gel formulation, concentrations of 2.113 ug/ml and 49.519 ug/ml salicylic acid were obtained in the epidermis and dermis respectively, whereas the Pheroid™ gel formulation showed salicylic acid, concentrations of 1.114 ug/ml in the epidermis and 95.360 ug/ml in the dermis. The cream formulation, however, depicted salicylic acid concentrations of 0.758 ug/ml in the epidermis and 44.729 ug/ml in the dermis. Lastly, after the Pheroid™ cream was applied, salicylic acid concentrations of 0.411 ug/ml and 48.424 ug/ml in the epidermis and dermis respectively, were measured. It could, therefore, be concluded that both niacinamide and salicylic acid tend to concentrate more in the dermis, irrespective of the formulation. This may be an advantage since acne is usually targeted in the dermis and epidermis. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2010.

Acne is a common skin disease that affects the follicular unit of the skin. Inflammatory- and noninflammatory forms of acne exist. The most affected areas on the body include the face, upper part of the chest and the back. These are the areas with the most sebaceous follicles. Acne occurs when hyperkeratinisation causes the cells of the hair follicle to shed too fast. These cells then block the follicle opening. Thus, sebum cannot pass through the hair follicle onto the skin. The human skin is composed of three layers, namely the epidermis, which acts as a waterproof layer and a barrier to infections; the dermis, which contains the skin appendages; and the subcutaneous fat layer. Skin acts as a protective layer against pathogens and damage to the body. It also provides a semi-impermeable barrier to prevent water loss. Azelaic acid and niacinamide are both currently used in the treatment of acne. Azelaic acid is a saturated dicarboxylic acid which is used to treat mild to moderate acne. It has antibacterial, keratolytic and comedolytic properties. Niacinamide, on the other hand, is the amide of nicotinic acid and is beneficial in the treatment of both papular and pustular acne. It has a demonstrated anti-inflammatory action and causes dose-dependent inhibition of sebocyte secretions. The Pheroid™ delivery system is a colloidal system that consists of even lipid-based submicron-and micron-sized structures that are very unique in nature. This technology is able to improve the absorption and/or efficacy of various active ingredients, as well as other compounds. In this study, a cream, Pheroid™ cream, a gel and a Pheroid™ gel were formulated, containing both azelaic acid and niacinamide. Stability tests were conducted on these formulations for six months, and it was established that none of the formulations were stable under the different storage conditions. Tests that were conducted during stability testing, as determined by the Medicines Control Council, included: assay, mass variation, appearance, viscosity, pH determination and confocal laser scanning microscopy (CLSM). Diffusion studies (12 hours long in total) with vertical Franz cells were conducted with Caucasian female skin obtained after abdominoplastic surgery. Tape-stripping followed in order to establish the epidermis and dermis concentrations of azelaic acid and niacinamide. Significant concentrations of both active ingredients were found in the epidermis and the dermis after 12 hours. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2010.

Extra pulmonary tuberculosis makes up 10% of all tuberculosis cases and cutaneous tuberculosis (CTB) only a fraction of this 10%. CTB is caused by mainly Mycobacterium tuberculosis and can lead to scarring and deformities. The disease presents in different forms, from superficial granulomas to deeper ulceration and necrosis. Tissue cultures, polymerase chain reactions or purified protein derivative staining is used for the diagnosis of CTB (Barbagallo etal., 2002:320). Since the current treatment for CTB is oral anti-tubercular regimens and no topical treatment is available yet (Barbagallo et a!., 2002:320), this study aims to provide a topical preparation of isoniazide and rifampicin which will prevent the deformities and scarring caused by CTB and deliver quicker healing. This topical preparation is to be used in addition to oral treatment. Isoniazide and rifampicin are powerful first-line anti-tubercular drugs, active against both intra- and extracellular bacteria (SAMF, 2005:293). Human skin is a resistant and protective barrier against the external environment and the stratum corneum is the main barrier against diffusion of compounds through the skin (Williams, 2003:9). The physicochemical characteristics (lipophilicity and molecular size) of neither isoniazide nor rifampicin are optimal for penetration of the stratum corneum and the skin-friendly Pheroid™ delivery system was incorporated in two of the formulations to investigate the possibility of improving drug delivery. In this study the transdermal delivery of isoniazide and rifampicin was studied after formulation into four different topical preparations. The stability of these formulations were determined over a six month period under three different conditions of temperature and humidity (25°C/60% RH (relative humidity), 30°C/60% RH and 40°C/75% RH). Isoniazide and rifampicin were formulated into two Pheroid™ and two non-Pheroid™ spray formulations: lotion, Pheroid™ lotion, emulgel and Pheroid™ emulgel. Micrographs were taken with a confocal laser scanning microscope and it was seen that the formulations were homogenous and oil droplets were smaller than 10 urn, allowing permeation through skin. Vertical Franz diffusion cells were used for in vitro permeation studies, with cellulose acetate membranes, for 12 h periods at pH 7.4, to determine drug release. The donor phase was the formulation, with 5 mg/ml of isoniazide and 10 mg/ml of rifampicin. The actives were released from the formulations and small concentrations penetrated the membranes. Release for isoniazide was best from the Pheroid™ emulgel and for rifampicin from the Pheroid™ lotion. Thus it can be concluded that the Pheroid™ improved drug release. The diffusion study was repeated, substituting the membranes with female abdominal skin in order to investigate transdermal delivery. Isoniazide and rifampicin failed to permeate the skin from any of the formulations and no isoniazide or rifampicin could be found in the skin by means of tape stripping after 12 h. Stability tests performed at 4, 8, 12 and 24 weeks was the determination of drug concentrations, pH, weight loss, viscosity, particle size, physical appearance and colour change tests. In these emulsion-type formulations, rifampicin proved to be more stable than isoniazide and after 24 weeks minimal concentrations of isoniazide (20.2 ug/ml) was left. The Pheroid™ formulations were proven to be more stable than the non-Pheroid™ formulations. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2010.

Extra pulmonary tuberculosis makes up 10% of all tuberculosis cases and cutaneous tuberculosis (CTB) only a fraction of this 10%. CTB is caused by mainly Mycobacterium tuberculosis and can lead to scarring and deformities. The disease presents in different forms, from superficial granulomas to deeper ulceration and necrosis. Tissue cultures, polymerase chain reactions or purified protein derivative staining is used for the diagnosis of CTB (Barbagallo etal., 2002:320). Since the current treatment for CTB is oral anti-tubercular regimens and no topical treatment is available yet (Barbagallo et a!., 2002:320), this study aims to provide a topical preparation of isoniazide and rifampicin which will prevent the deformities and scarring caused by CTB and deliver quicker healing. This topical preparation is to be used in addition to oral treatment. Isoniazide and rifampicin are powerful first-line anti-tubercular drugs, active against both intra- and extracellular bacteria (SAMF, 2005:293). Human skin is a resistant and protective barrier against the external environment and the stratum corneum is the main barrier against diffusion of compounds through the skin (Williams, 2003:9). The physicochemical characteristics (lipophilicity and molecular size) of neither isoniazide nor rifampicin are optimal for penetration of the stratum corneum and the skin-friendly Pheroid™ delivery system was incorporated in two of the formulations to investigate the possibility of improving drug delivery. In this study the transdermal delivery of isoniazide and rifampicin was studied after formulation into four different topical preparations. The stability of these formulations were determined over a six month period under three different conditions of temperature and humidity (25°C/60% RH (relative humidity), 30°C/60% RH and 40°C/75% RH). Isoniazide and rifampicin were formulated into two Pheroid™ and two non-Pheroid™ spray formulations: lotion, Pheroid™ lotion, emulgel and Pheroid™ emulgel. Micrographs were taken with a confocal laser scanning microscope and it was seen that the formulations were homogenous and oil droplets were smaller than 10 urn, allowing permeation through skin. Vertical Franz diffusion cells were used for in vitro permeation studies, with cellulose acetate membranes, for 12 h periods at pH 7.4, to determine drug release. The donor phase was the formulation, with 5 mg/ml of isoniazide and 10 mg/ml of rifampicin. The actives were released from the formulations and small concentrations penetrated the membranes. Release for isoniazide was best from the Pheroid™ emulgel and for rifampicin from the Pheroid™ lotion. Thus it can be concluded that the Pheroid™ improved drug release. The diffusion study was repeated, substituting the membranes with female abdominal skin in order to investigate transdermal delivery. Isoniazide and rifampicin failed to permeate the skin from any of the formulations and no isoniazide or rifampicin could be found in the skin by means of tape stripping after 12 h. Stability tests performed at 4, 8, 12 and 24 weeks was the determination of drug concentrations, pH, weight loss, viscosity, particle size, physical appearance and colour change tests. In these emulsion-type formulations, rifampicin proved to be more stable than isoniazide and after 24 weeks minimal concentrations of isoniazide (20.2 ug/ml) was left. The Pheroid™ formulations were proven to be more stable than the non-Pheroid™ formulations. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2010.

This thesis investigates the statistical properties of Kernel Smoothed Empirical Likelihood (KSEL, e.g. Smith, 1997 and 2004) estimator and various associated inference procedures in weakly dependent data. New tests for structural stability are proposed and analysed. Asymptotic analyses and Monte Carlo experiments are applied to assess these new tests, theoretically and empirically. Chapter 1 reviews and discusses some estimation and inferential properties of Empirical Likelihood (EL, Owen, 1988) for identically and independently distributed data and compares it with Generalised EL (GEL), GMM and other estimators. KSEL is extensively treated, by specialising kernel-smoothed GEL in the working paper of Smith (2004), some of whose results and proofs are extended and refined in Chapter 2. Asymptotic properties of some tests in Smith (2004) are also analysed under local alternatives. These special treatments on KSEL lay the foundation for analyses in Chapters 3 and 4, which would not otherwise follow straightforwardly. In Chapters 3 and 4, subsample KSEL estimators are proposed to assist the development of KSEL structural stability tests to diagnose for a given breakpoint and for an unknown breakpoint, respectively, based on relevant work using GMM (e.g. Hall and Sen, 1999; Andrews and Fair, 1988; Andrews and Ploberger, 1994). It is also original in these two chapters that moment functions are allowed to be kernel-smoothed after or before the sample split, and it is rigorously proved that these two smoothing orders are asymptotically equivalent. The overall null hypothesis of structural stability is decomposed according to the identifying and overidentifying restrictions, as Hall and Sen (1999) advocate in GMM, leading to a more practical and precise structural stability diagnosis procedure. In this framework, these KSEL structural stability tests are also proved via asymptotic analysis to be capable of identifying different sources of instability, arising from parameter value change or violation of overidentifying restrictions. The analyses show that these KSEL tests follow the same limit distributions as their counterparts using GMM. To examine the finite-sample performance of KSEL structural stability tests in comparison to GMM's, Monte Carlo simulations are conducted in Chapter 5 using a simple linear model considered by Hall and Sen (1999). This chapter details some relevant computational algorithms and permits different smoothing order, kernel type and prewhitening options. In general, simulation evidence seems to suggest that compared to GMM's tests, these newly proposed KSEL tests often perform comparably. However, in some cases, the sizes of these can be slightly larger, and the false null hypotheses are rejected with much higher frequencies. Thus, these KSEL based tests are valid theoretical and practical alternatives to GMM's.

<p>The symmetry requirements of both second harmonic generation (SHG) and triboluminescence (TL) provide outstanding selectivity to noncentrosymmetric crystals, leading to high signal to noise measurements of crystal growth and nucleation of active pharmaceutical ingredients (API) within amorphous solid dispersions (ASD) during accelerated stability testing. ASD formulations are becoming increasingly popular in the pharmaceutical industry due to their ability to address challenges associated with APIs that suffer from poor dissolution kinetics and low bioavailability as a result of low aqueous solubility. ASDs kinetically trap APIs into an amorphous state by dispersing the API molecules within a polymer matrix. The amorphous state of the API leads to an increase in apparent solubility, faster dissolution kinetics, and an increase in bioavailability. Both SHG and TL are used to quantitatively and qualitatively detect the crystal growth and nucleation within ASD formulations at the parts per million (ppm) regime. TL is the emission of light upon mechanical disruption of a piezoelectrically active crystal. Instrumentation was developed to rapidly determine the qualitative presence of crystals within nominally amorphous pharmaceutical materials in both powders and slurries. SHG was coupled with a controlled environment for <i>in situ</i> stability testing (CEiST) to enable <i>in situ</i> accelerated stability testing of ASDs. Single particle tracking enabled by the CEiST measurements provided insights into crystal growth rate distributions present due to local differences within the material. Accelerated stability testing monitored by <i>in situ</i> measurements increased the signal to noise in recovered nucleation and crystal growth rates by suppressing the Poisson noise normally present within conventional accelerated stability tests. The disparities between crystal growth and nucleation kinetics on the surface versus within bulk material were also investigated by single particle tracking and <i>in situ </i>measurements. Crystals were found to grow faster in the bulk compared to single crystals growing on the surface while total crystallinity was found to be higher on the surface due to radial growth habits of crystals on the surface compared to columnar growth within the bulk. To increase the throughput of the <i>in situ </i>measurements, a temperature and relative humidity array (TRHA) was developed. The TRHA utilizes a temperature gradient and many individual liquid wells to enable the use of a multitude of different conditions at the same time which can reduce time required to inform formulations design of stability information. </p>

In this work a method for determination of canagliflozin and its degradation products by HPLC with UV and MS detector was developed. The developed method was used to study the forced degradation of canagliflozin and to investigate the major degradation products resulting from exposure of canagliflozin to oxidative stress. Canagliflozin is a phenolic glycoside derivative and a glucose-sodium transporter 2 inhibitor that stimulates urinary glucose excretion by suppressing glucose reabsorption from the proximal tubule in the kidneys. Canagliflozin is used to control blood glucose levels in patients with type 2 diabetes. In an optimized method, an Agilent Poroshell 120 SB-Aq (2.1 × 100 mm, 2.7 µm) column was used and a mixture of buffer (10mM HCOOH adjusted with ammonium hydroxide to pH 3.5) and acetonitrile as a mobile phase. The method validation included testing of accuracy, repeatability, the limit of detection and quantification, linearity and linear dynamic range, the robustness of the method, and testing of sample stability. The limit of detection of the method was 8.9·10-5 mg ml-1 (2.0·10-7 mol l-1 ) and the limit of quantification was 3.0·10-4 mg ml-1 (6.8·10-7 mol l-1 ). At a concentration of 0.3 mg ml-1 , the repeatability (n = 7) was 0.17 % and 0.75 % for the retention time and the peak...

Pyrolysis oil is known to be unstable due to polycondensation reactions that negatively affect properties, such as increased viscosity and water content, lower heating values, and phase separation. Filtration of particulates and solid content out of the pyrolysis oil has been proven to increase stability, thus a filtration system was designed for pilot scale testing for the Mississippi State University Sustainable Energy Research Center (SERC). A literature review was conducted to determine potentially effective methods and eliminate methods likely to not improve the pyrolysis oil properties and stability. An in-line centrifuge system was identified as a useful and cost effective way to remove solids from the pyrolysis oil with an added benefit of potentially removing water content through a three-phase separation configuration. Lab-scale testing of centrifugation on pyrolysis oil indicated both two phase (solid + oil phases) and three phase (solid + aqueous phase + oil phases) separations could be obtained depending on feedstock and pyrolysis oil characteristics, and that centrifugation was a viable option for the removal of solid content. KiOR, Inc. pine clear wood derived pyrolysis oil (formerly known as ReCrude™) was characterized to determine physicochemical properties in comparison to literature results. Aging tests were also performed to investigate stability. In comparison with literature data, the properties for the KiOR product indicated significantly lower water content, particulate matter loading, and viscosity coupled with higher heating and pH values, indicating a product much closer in composition to fossil fuel oils than other pyrolysis oils. The KiOR ReCrudeM™ oil also demonstrated a much higher degree of stability versus other pyrolysis oils; however, there are still some stability issues with the aged samples resulting in slightly higher water content and viscosity values and lower heating and pH values. It is recommended that stability testing (aging) be performed on aliquots separated using a method such as rotary evaporation to more accurately determine what mechanisms are resulting in the properties changes observed over time in response to elevated temperature and/or pressure.

Several design equations for predicting the capacity of a single-headed anchor bolt embedded in plain concrete have been recommended in the United States. The capacities computed by these different recommendations, in some cases, differ significantly. The existing differences in current design criteria for anchor bolts subjected to tensile or shear loading is discussed with emphasis on the ACI, the PCI and the proposed Load and Resistance Factor Design (LRFD) equations. Available data from test results on the anchor bolts and welded studs were analyzed. Then, based on the analysis of these data and statistical information on basic design variables, a reliability analysis was performed. Using the advanced first-order second-moment reliability analysis method, risk levels implied in these design equations were computed for a dead and maximum live load combination. It was found that there are inconsistencies in the levels of safety implied by both the ACI and the PCI design equations, and that the level of safety depends on the loading and the failure mode under consideration. By comparing reliability indices for these design equations, it is thus possible to make an objective evaluation of current design criteria. / Master of Science

Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2007.