In this study the stability and nutrient removal performance of aerobic granules under variable operating pH and variable growth medium was investigated. The results indicated that alkaline pH (pH=9) inhibited nitrogen and phosphorus removal. Moreover, high pH induced granules breakage and resulted in an increased biomass concentration in the effluent. On the other hand, acidic pH (pH=6) did not have significant impacts on stability and nutrient removal efficiency of granules. Changing the growth medium from acetate-based wastewater to municipal wastewater resulted in loss of biological phosphorus removal while ammonium and COD removal stayed the same. The granules disintegrated during the first two weeks after changing the feed; re-granulation of the biomass was observed after the acclimation of bacteria to the new growth medium. However, the granules breakage did not exert significant impact on settling property of biomass.

Slope instabilities have been affecting the grade slope of Provincial Trunk Highway 5 near the junction with Provincial Trunk Highway 10 in northwestern Manitoba for over 50 years. In recent years, the instabilities have resulted in significant damage to the highway pavement surface. In 2011, Manitoba Infrastructure and Transportation initiated a geotechnical investigation to gain a better understanding of the failure, identify possible failure mechanisms, and explore various remedial design alternatives in order to stabilize the slope. The site was instrumented with slope inclinometers and vibrating wire piezometers, and monitored over a period of two years. An extensive laboratory testing program was completed to compare the results of direct shear tests and torsional ring shear tests for determining the shear strength of the underlying Cretaceous clay shale. Measured values were compared with values back analyzed using limit equilibrium analysis. A coupled finite element model was used to model the expected excess porewater pressure response, and therefore the stability of the slope, during construction of a stabilization berm. It was subsequently calibrated to agree with the measured porewater pressure responses from the instrumentation. Finally, spring flood conditions were simulated to determine the effect of multiple flash flood events on the stability of the slope.

Numerical simulations of the Navier-Stokes equations are conducted to achieve a better understanding of the behavior of wakes generated by the wind turbines. The simulations are performed by combining the in-house developed code EllipSys3D with the actuator line technique. In step one of the project, a numerical study is carried out focusing on the instability onset of the trailing tip vortices shed from a 3-bladed wind turbine. To determine the critical frequency, the wake is perturbed using low-amplitude excitations located near the tip spirals. Two basic flow cases are studied; symmetric and asymmetric setups. In the symmetric setup a 120 degree flow symmetry condition is dictated due to the confining the polar computational grid to 120 degree or introducing identical excitations. In the asymmetric setup, uncorrelated excitations are imposed near the tip of the blades. Both setups are analyzed using proper orthogonal decomposition (POD) and dynamic mode decomposition (DMD). By analysing the dominant modes, it was found that in the symmetric setup the amplification of specific waves (traveling structures) traveling along the tip vortex spirals is responsible for triggering the instability leading to wake breakdown, while by breaking the symmetry almost all the modes are involved in the tip vortex destabilization. The presence of unstable modes in the wake is related to the mutual inductance (vortex pairing) instability where there is an out-of-phase displacement of successive helix turns. Furthermore, using the non-dimensional growth rate, it is found that the mutual inductance instability has a universal growth rate equal to Π/2. Using this relationship, and the assumption that breakdown to turbulence occurs once a vortex has experienced sufficient growth, an analytical relationship is provided for determining the length of the stable wake. This expression shows that the stable wake length is inversely proportional to thrust, tip speed ratio and the logarithmic of the turbulence intensity. In second study, large eddy simulations of the Navier-Stokes equations are also performed to investigate the wake interaction. Previous actuator line simulations on the single model wind turbine show that the accuracy of the results is directly related to the quality of the input airfoil characteristics. Therefore, a series of experiments on a 2D wing are conducted to obtain high quality airfoil characteristics for the NREL S826 at low Reynolds numbers. The new measured data are used to compute the rotor performance. The results show that the power performance as well as the wake development behind the rotor are well-captured. There are, however, some difficulties in prediction of the thrust coefficients. The continuation of this work considers the wake interaction investigations of two turbines inline (full-wake interaction) and two turbines with spanwise offset (half wake interaction). It is demonstrated that the numerical computations are able to predict the rotor performances as well as the flow field around the model rotors, and it can be a suitable tool for investigation of the wind turbine wakes. In the last study, an evaluation of the performance and near-wake structure of an analytical vortex model is presented. The vortex model is based on the constant circulation along the blades (Joukowsky rotor) and it is able to determine the geometry of the tip vortex filament in the rotor wake, allowing the free wake expansion and changing the local tip vortex pitch. Two different wind turbines have been simulated: a wind turbine with constant circulation along the blade and the other setup with a realistic circulation distribution, to compare the outcomes of the vortex model with real operative wind turbine conditions. The vortex model is compared with the actuator line approach and the presented comparisons show that the vortex method is able to approximate the single rotor performance and qualitatively describe the flow field around the wind turbine but with a negligible computational effort. This suggests that the vortex model can be a substitute of more computationally-demanding methods like actuator line technique to study the near-wake behavior. / <p>QC 20141010</p>

This work describes the development of a microfluidic platform that can be used to study suspension stability and crystallization with in droplets as a function of time and concentration. Techniques for monodisperse droplet formation, droplet trapping and storage, and droplet dehydration are developed and used to design a microfluidic platform that can be adapted for the applications of interest. A geometric model is developed to predict the droplet shape and emulsion structure generated by microfluidic nozzles. However, droplet volume and structure spacing cannot be independently controlled using microfluidic nozzles, and a design consisting of an array of traps is considered to achieve the desired structure for stable, extended droplet observation. The dehydration of aqueous droplets stored in the array is characterized as a function of relative humidity, and is shown to be reasonably estimated as a species diffusing from a sphere into an infinite medium. The microfluidic platform for droplet dehydration is combined with particle tracking to show that the stability of particle suspensions can be probed as a function of salt concentration. The flocculation behavior observed in the trapped droplets agrees well with corresponding macroscale measurements as well as with previously published studies. The platform is also used to generate substantial sample sizes to measure nucleation statistics and crystal growth rates of glycine as a function of initial concentration, environmental conditions, and the presence of additives. These applications show proof of concept that the microfluidic platform is a useful tool for the analysis of the behavior observed during particle aggregation and crystallization.

the 18th World Congress The International Federation of Automatic Control, Milano (Italy), August 28 - September 2, 2011

This thesis proposes a control strategy for small-signal dynamic stability enhancement of a DC-segmented AC power system. This control strategy provides four control schemes based on HVDC supplementary control or modification of the operational condition of the HVDC control system to improve the system stability by (i) damping the oscillations within a segment using supplementary current control of a line-commutated HVDC link, based on the model predictive control (MPC) method (control scheme 1), (ii) minimizing the propagation of dynamics among the segments based on a coordinated linear quadratic Gaussian (LQG)-based supplementary control (control scheme 2), (iii) selectively distributing the oscillations among the segments based on a coordinated LQG-based supplementary control (control scheme 3) and (iv) changing the set-points of the HVDC control system in the direction determined based on the sensitivities of the Hopf stability margin to the HVDC links set-points (control scheme 4). Depending on the system characteristics, one or more of the proposed control schemes may be effective for mitigating the system oscillations. Study results show that (i) control scheme 1 leads to damped low-frequency oscillations and provides fast recovery times after faults, (ii) under control scheme 2, each segment in a DC-segmented system can experience major disturbances without causing adjacent segments to experience the disturbances with the same degree of severity, (iii) control scheme 3 enables the controlled propagation of the oscillations among segments and damps out the oscillatory dynamics in the faulted segment, and (iv) control scheme 4 improves the stability margin for Hopf bifurcations caused by various events. Since power system software tools exhibit limitations for advanced control design, this thesis also presents a methodology based on MATLAB/Simulink software to (i) systematically construct the nonlinear differential-algebraic model of an AC-DC system, and (ii) automatically extract a linearized state space model of the system for the design of the proposed control schemes. The nonlinear model also serves as a platform for the time-domain simulation of power system dynamics. The accuracy of the MATLAB/Simulink-based AC-DC power system model and time-domain simulation platform is validated by comparison against PSS/E.

Acquired immunodeficiency syndrome (AIDS) has shown a rapid increase in incidence over the past 25 years. Many clinical manifestations occur in patients infected with human immunodeficiency virus (HIV) due to compromised immunity caused by this virus. Dermatological disorders are almost inevitable for individuals suffering from HIV/AIDS and are seen in approximately 90% of all infected patients (Cedeno-Laurent et al., 2011:5; Dlova & Mosam, 2004:12). Vulnerability of the skin causes impaired life quality by causing low self-esteem, depression or even suicide. The skin is regarded as the most visible organ due to its location and large surface area (Cedeno-Laurent et al., 2011:5). Cutaneous manifestations, including viral, fungal and bacterial pathogens, can serve as markers in HIV/AIDS progression or as indicators for commencing HIV/AIDS treatment (Vusadevan et al., 2012:20). Acyclovir is an anti-viral agent showing activity against herpes simplex virus type 1 and type 2, varicella-zoster virus and cytomegalovirus to a certain extent (King, 1988:176; Beers, 2006:1061). The anti-fungal agent, ketoconazole, shows activity against the majority of pathogenic fungal infections seen in HIV/AIDS including Candida spp, Cryptocococcus neoformans and Histoplasma capsulatum (Bennet, 2006:1225). Ketoconazole has shown to have in vitro inhibitory activity against certain Staphylococcus spp (Pottage, 1986:217). According to Bickers (1994:89), ketoconazole shows a synergistic anti-viral activity when used in combination with acyclovir. Using the mucosal route of administration may be beneficial for these compounds due to the location of occurrence as many of these diseases are found on mucosal surfaces such as the labial and vaginal areas. Compounds are mainly delivered via passive diffusion across epithelium membranes (Patel et al., 2011:107). In mucosal skin, the principle barrier function is removed by the absence of the keratinised stratum corneum as found in normal skin and is, thus, more permeable (Farage & Scheffler, 2011:117). In this study three different formulations containing acyclovir (5% w/w) and ketoconazole (2% w/w) were formulated for topical delivery on mucus membranes, which included a cream, gel and lip balm. Topical delivery is used to target specific sites on the skin by penetration of the skin layers, but has a minimal requirement for systemic effect (Dayan, 2005:67). The aim in this study was to formulate a stable product containing acyclovir and ketoconazole that would provide an efficient flux of both compounds when applied on mucosal membranes. In vitro studies were performed to determine skin permeation of acyclovir and ketoconazole by using a flow-through diffusion system. The formulated products were compared to Acitop® and Ketazol®, which are two products available on the South African market, containing acyclovir and ketoconazole, respectively. However, no product is yet available containing both acyclovir and ketoconazole. Results obtained for acyclovir released from the different formulations during the permeation studies depicted no statistical significant differences between the different formulations in the average cumulative amount of acyclovir released (p > 0.05). The cream, gel and lip balm formulations depicted a decreased average cumulative acyclovir amount released through the mucosa when compared to Acitop®. The following rank order could be established: Acitop® > gel > cream > lip balm. Furthermore, the gel formulation and Acitop® produced a relatively similar percentage of acyclovir diffused. A linear relationship (r2 = 0.9977) existed between the flux and the release rate of acyclovir from the different formulations, indicating that as the acyclovir was released, the flux increased correspondingly. Using the Higuchi model, the average cumulative amount of acyclovir released that permeated the mucosa per unit surface area was constructed against the square root of time (h½). All formulations depicted a correlation coefficient (r2) of 0.9644 – 0.9914 for acyclovir, indicating that the release of acyclovir from the different formulations could be described by the Higuchi model. No statistical significant differences could be obtained for acyclovir between any of the formulations for % diffused, apparent release constant (ARC), release rate (RR) and lag times. The amount of ketoconazole that permeated the mucosa from the gel and cream formulations exhibited a smaller average cumulative amount that permeated the mucosa when compared to Ketazol®. The lip balm was the only formulation that showed a statistically significant (p < 0.05) increase in permeation through the mucosa in comparison to Ketazol®. A rank order for the average cumulative amount of ketoconazole that permeated through the mucosa could be established namely: lip balm >>> Ketazol® > gel > cream. A linear relationship (r2 = 0.9991) was depicted between the average release constant and the average release rate from each of the different formulations for ketoconazole. This indicated that as the compound was released, the flux increased correspondingly which was in accordance with the acyclovir release tendency. The only statistically significant difference (p < 0.05) was seen for the release rate of ketoconazole from the lip balm formulation compared to that of the cream and gel formulations. Release rate and flux of ketoconazole was the highest from the lip balm formulation. The rate of ketoconazole released from all of the different formulations obeyed the Higuchi model as the amount of compound released from each formulation was a linear function of the square root of time (r2 = 0.9584 - 0.9899). Statistically significant (p < 0.05) differences were furthermore noted between the lip balm and both the cream and gel formulations when % diffused, ARC and RR were compared. The lip balm depicted the highest percentage diffused, the highest ARC as well as the fastest RR. However, no statistical differences were obtained between the cream and gel formulation even though the gel formulation performed slightly better. Considering the lag time, all the formulations presented with a relatively shorter initial time of release (less than an hour). Shorter lag time values indicate that the ketoconazole was preferentially released by the base of the formulations. Statistically significant differences (p < 0.05) were depicted between the lag times of Ketazol® and lip balm formulation, as well as between the lip balm and the cream and gel formulations. The stability of the formulated products was examined over a period of three months according to the standards of the International Conference of Harmonisation (ICH) Tripartite Guidelines (2003:12) and the Medicines Control Council (MCC) of South Africa (2011:12). Each of the formulated products was stored at three different temperatures and humidities. Stability tests conducted included visual appearance, mass variation, assay, pH determination, viscosity, particle size observation, and zeta potential. Due to the different properties of the formulations, some tests could not be conducted on the gel and lip balm formulations. The outcomes of the stability tests showed that all three formulations presented acceptable results for some of the tests conducted. No significant changes were noted in the visual appearance, mass variation and pH values of all tested formulations at the specified storage conditions. Acyclovir is slightly soluble in water and has a solubility of 1.3 mg/ml at 25 ºC according to Bethesda (2010). Low solubility often causes crystal formation in products. All of the formulations developed in this study presented crystals on the surface. Due to non-homogenous sample preparation differences in concentrations could be obtained as the amount and size of crystals may differ. Ketoconazole did, however, not depict any significant changes in concentration for any of the formulations at all storage conditions. The cream depicted variable changes in viscosity over the three months, showing no clear trend, whereas, the viscosity measurement results of the gel formulation depicted a definite trend. The sodium carboxymethylcellulose (Na-CMC) used as the thickening agent in this formulation was responsible for this trend obtained in the results, due to the effects of pH, hydration and temperature on this excipient (Aqualon, 1996:10). Results obtained from zeta potential determination for the cream formulation depicted no significant change and the values remained below 25 mV. Zeta potential values below 25 mV present the risk of coalescence due to the lower repelling forces between particles (Jelvehgari et al., 2010:1240). The average size of the particles in dispersion was also observed and could be linked to zeta potential values. The cream depicted an increase in particle size over the three months stability testing. Due to the low zeta potential depicted in the cream formulation it was expected that coalescence would occur over time. From results obtained in this study it was clear that manufacturing different formulations containing both acyclovir and ketoconazole proved difficult due to the significant differences between their physicochemical properties, which in turn influenced the stability of the formulation. Furthermore, it was evident that formulation at specific pH values, as well as the incorporation of certain excipients, played a significant role in the stability of formulations. / Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013

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

Acquired immunodeficiency syndrome (AIDS) has shown a rapid increase in incidence over the past 25 years. Many clinical manifestations occur in patients infected with human immunodeficiency virus (HIV) due to compromised immunity caused by this virus. Dermatological disorders are almost inevitable for individuals suffering from HIV/AIDS and are seen in approximately 90% of all infected patients (Cedeno-Laurent et al., 2011:5; Dlova & Mosam, 2004:12). Vulnerability of the skin causes impaired life quality by causing low self-esteem, depression or even suicide. The skin is regarded as the most visible organ due to its location and large surface area (Cedeno-Laurent et al., 2011:5). Cutaneous manifestations, including viral, fungal and bacterial pathogens, can serve as markers in HIV/AIDS progression or as indicators for commencing HIV/AIDS treatment (Vusadevan et al., 2012:20). Acyclovir is an anti-viral agent showing activity against herpes simplex virus type 1 and type 2, varicella-zoster virus and cytomegalovirus to a certain extent (King, 1988:176; Beers, 2006:1061). The anti-fungal agent, ketoconazole, shows activity against the majority of pathogenic fungal infections seen in HIV/AIDS including Candida spp, Cryptocococcus neoformans and Histoplasma capsulatum (Bennet, 2006:1225). Ketoconazole has shown to have in vitro inhibitory activity against certain Staphylococcus spp (Pottage, 1986:217). According to Bickers (1994:89), ketoconazole shows a synergistic anti-viral activity when used in combination with acyclovir. Using the mucosal route of administration may be beneficial for these compounds due to the location of occurrence as many of these diseases are found on mucosal surfaces such as the labial and vaginal areas. Compounds are mainly delivered via passive diffusion across epithelium membranes (Patel et al., 2011:107). In mucosal skin, the principle barrier function is removed by the absence of the keratinised stratum corneum as found in normal skin and is, thus, more permeable (Farage & Scheffler, 2011:117). In this study three different formulations containing acyclovir (5% w/w) and ketoconazole (2% w/w) were formulated for topical delivery on mucus membranes, which included a cream, gel and lip balm. Topical delivery is used to target specific sites on the skin by penetration of the skin layers, but has a minimal requirement for systemic effect (Dayan, 2005:67). The aim in this study was to formulate a stable product containing acyclovir and ketoconazole that would provide an efficient flux of both compounds when applied on mucosal membranes. In vitro studies were performed to determine skin permeation of acyclovir and ketoconazole by using a flow-through diffusion system. The formulated products were compared to Acitop® and Ketazol®, which are two products available on the South African market, containing acyclovir and ketoconazole, respectively. However, no product is yet available containing both acyclovir and ketoconazole. Results obtained for acyclovir released from the different formulations during the permeation studies depicted no statistical significant differences between the different formulations in the average cumulative amount of acyclovir released (p > 0.05). The cream, gel and lip balm formulations depicted a decreased average cumulative acyclovir amount released through the mucosa when compared to Acitop®. The following rank order could be established: Acitop® > gel > cream > lip balm. Furthermore, the gel formulation and Acitop® produced a relatively similar percentage of acyclovir diffused. A linear relationship (r2 = 0.9977) existed between the flux and the release rate of acyclovir from the different formulations, indicating that as the acyclovir was released, the flux increased correspondingly. Using the Higuchi model, the average cumulative amount of acyclovir released that permeated the mucosa per unit surface area was constructed against the square root of time (h½). All formulations depicted a correlation coefficient (r2) of 0.9644 – 0.9914 for acyclovir, indicating that the release of acyclovir from the different formulations could be described by the Higuchi model. No statistical significant differences could be obtained for acyclovir between any of the formulations for % diffused, apparent release constant (ARC), release rate (RR) and lag times. The amount of ketoconazole that permeated the mucosa from the gel and cream formulations exhibited a smaller average cumulative amount that permeated the mucosa when compared to Ketazol®. The lip balm was the only formulation that showed a statistically significant (p < 0.05) increase in permeation through the mucosa in comparison to Ketazol®. A rank order for the average cumulative amount of ketoconazole that permeated through the mucosa could be established namely: lip balm >>> Ketazol® > gel > cream. A linear relationship (r2 = 0.9991) was depicted between the average release constant and the average release rate from each of the different formulations for ketoconazole. This indicated that as the compound was released, the flux increased correspondingly which was in accordance with the acyclovir release tendency. The only statistically significant difference (p < 0.05) was seen for the release rate of ketoconazole from the lip balm formulation compared to that of the cream and gel formulations. Release rate and flux of ketoconazole was the highest from the lip balm formulation. The rate of ketoconazole released from all of the different formulations obeyed the Higuchi model as the amount of compound released from each formulation was a linear function of the square root of time (r2 = 0.9584 - 0.9899). Statistically significant (p < 0.05) differences were furthermore noted between the lip balm and both the cream and gel formulations when % diffused, ARC and RR were compared. The lip balm depicted the highest percentage diffused, the highest ARC as well as the fastest RR. However, no statistical differences were obtained between the cream and gel formulation even though the gel formulation performed slightly better. Considering the lag time, all the formulations presented with a relatively shorter initial time of release (less than an hour). Shorter lag time values indicate that the ketoconazole was preferentially released by the base of the formulations. Statistically significant differences (p < 0.05) were depicted between the lag times of Ketazol® and lip balm formulation, as well as between the lip balm and the cream and gel formulations. The stability of the formulated products was examined over a period of three months according to the standards of the International Conference of Harmonisation (ICH) Tripartite Guidelines (2003:12) and the Medicines Control Council (MCC) of South Africa (2011:12). Each of the formulated products was stored at three different temperatures and humidities. Stability tests conducted included visual appearance, mass variation, assay, pH determination, viscosity, particle size observation, and zeta potential. Due to the different properties of the formulations, some tests could not be conducted on the gel and lip balm formulations. The outcomes of the stability tests showed that all three formulations presented acceptable results for some of the tests conducted. No significant changes were noted in the visual appearance, mass variation and pH values of all tested formulations at the specified storage conditions. Acyclovir is slightly soluble in water and has a solubility of 1.3 mg/ml at 25 ºC according to Bethesda (2010). Low solubility often causes crystal formation in products. All of the formulations developed in this study presented crystals on the surface. Due to non-homogenous sample preparation differences in concentrations could be obtained as the amount and size of crystals may differ. Ketoconazole did, however, not depict any significant changes in concentration for any of the formulations at all storage conditions. The cream depicted variable changes in viscosity over the three months, showing no clear trend, whereas, the viscosity measurement results of the gel formulation depicted a definite trend. The sodium carboxymethylcellulose (Na-CMC) used as the thickening agent in this formulation was responsible for this trend obtained in the results, due to the effects of pH, hydration and temperature on this excipient (Aqualon, 1996:10). Results obtained from zeta potential determination for the cream formulation depicted no significant change and the values remained below 25 mV. Zeta potential values below 25 mV present the risk of coalescence due to the lower repelling forces between particles (Jelvehgari et al., 2010:1240). The average size of the particles in dispersion was also observed and could be linked to zeta potential values. The cream depicted an increase in particle size over the three months stability testing. Due to the low zeta potential depicted in the cream formulation it was expected that coalescence would occur over time. From results obtained in this study it was clear that manufacturing different formulations containing both acyclovir and ketoconazole proved difficult due to the significant differences between their physicochemical properties, which in turn influenced the stability of the formulation. Furthermore, it was evident that formulation at specific pH values, as well as the incorporation of certain excipients, played a significant role in the stability of formulations. / Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013

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