The development, manufacture and evaluation of a selfmicro-emulsifying drug delivery system for efavirenz
- Authors: Musakana, Tanyaradzwa Gracious
- Date: 2018
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/62643 , vital:28223
- Description: Expected release date-April 2020
- Full Text:
- Date Issued: 2018
An energy, water and disease disaster management module: a technoeconomic feasibility analysis
- Authors: Nicholson, Thomas J
- Date: 2017
- Language: English
- Type: text , Thesis , Masters , MSC
- Identifier: http://hdl.handle.net/10962/65167 , vital:28700
- Description: Intermittent energy and water supply are current challenges faced by many residents in South Africa. South Africa is one of the more water scarce countries in the world; this coupled with the lack of infrastructure makes it challenging to provide every citizen with their right to basic water and sanitation. With millennium development goal 7C not being addressed in many areas, residents experience sub-standard living conditions, which drastically increases the vulnerability of marginalised groups to epidemics. In the sustainable development goals improving sanitation and drinking water has been identified as one of the most effective and least expensive means of reducing fatalities and increasing public health. There is a need for a mobile laboratory that demonstrates power and water self-sufficiency, which is capable of on-site diagnosis and water treatment. The unit will have the ability to perform independent compliance monitoring of municipal water supply, treat inadequate water and provide surplus electricity to surrounding areas. A literature-based study was performed utilizing several scientific databases to identify current methods of power and water production in previous disaster management and humanitarian relief situations. Based on findings three example laboratories were theoretically designed; structural modelling, systems simulation and optimization and sensitivity analyses were performed with HOMER Pro, PackVol and SketchUp. A cost benefit analysis was performed with the social return on investment methodology. Novel human waste processing was performed with fly ash and simulated faeces. Bacterial species identification in ice samples was performed with the API 20E protocol and limited equipment as a proof of concept for field deployment. A hybrid system consisting of PV panels, a wind turbine and biomass generator showed promise for displaced humanitarian relief camps; with every 1 ZAR capital invested resulting in 3.13 ZAR social benefit. A system consisting of PV panels and a battery bank proved to have the least environmental impact and the grid supply laboratory showed a cheaper cost of energy alternative for needs provision. Fly ash showed potential as in nutrient recovery and as a fertility aid to soil. The units developed function as a means to increase disaster preparedness and humanitarian relief as well a means to improve quality of life for rural marginalize populations.
- Full Text:
- Date Issued: 2017
Development and validation of an In Vitro Release Test (IVRT) to investigate the release of miconazole nitrate from topical cream formulations
- Authors: Purazi, Potiwa
- Date: 2017
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/65223 , vital:28711
- Description: Expected release date-May 2019
- Full Text:
- Date Issued: 2017
Evaluation of the acceptability of ambulatory blood pressure monitoring in a semi-rural, Eastern Cape population
- Authors: Chiwanza, Farisai
- Date: 2017
- Language: English
- Type: text , Thesis , Masters , MPharm
- Identifier: http://hdl.handle.net/10962/59161 , vital:27447
- Description: Expected release date-April 2019
- Full Text:
- Date Issued: 2017
Formulation, development and evaluation of lipid nanocarriers for minocycline hydrochloride
- Authors: Ranchhod, Janeeta
- Date: 2017
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/65234 , vital:28712
- Description: Expected release date-May 2019
- Full Text:
- Date Issued: 2017
Investigation of the potency of topical corticosteroids using the vasoconstrictor assay
- Authors: Zvidzayi, Kudzayi Michael
- Date: 2017
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/65279 , vital:28717
- Description: Expected release date-May 2019
- Full Text:
- Date Issued: 2017
Microbial water quality monitoring of raw and treated water sources in Harare and the effect of gender in disaster management due to water related disasters
- Authors: Chirenda, Tatenda Grace
- Date: 2017
- Subjects: Drinking water Microbiology Zimbabwe Harare , Heterotrophic bacteria Zimbabwe Harare , Emergency management Zimbabwe Harare , Disasters Social aspects Zimbabwe Harare , Water quality management Zimbabwe Harare , Public health Zimbabwe Harare , Sex role Zimbabwe Harare
- Language: English
- Type: text , Thesis , Masters , MPharm
- Identifier: http://hdl.handle.net/10962/59156 , vital:27444
- Description: Background - Microbial water quality monitoring is essential to the provision of potable water for domestic use. Unsafe water sources increase the risk of waterborne diseases. There is a need to raise awareness of legislature that supports management of water related disasters. Gender, education, health, and economic vulnerability contribute to the success of disaster management. Aim - This study aimed to investigate the microbial water quality of treated water in the Harare area. The study also researched the microbial water quality monitoring practices in Zimbabwe and how these contribute to the management of water borne diseases. The impact of gender, marriage, education, and disease in disaster management practices in Zimbabwe and South Africa was analysed. Method - Literature review was conducted on microbial water quality monitoring practices in Zimbabwe and legislature that supports disaster management. Practices of disaster management in Zimbabwe, and South Africa were investigated and compared. The perspective of the Harare community on the quality of their potable water was investigated through the use of a questionnaire and water quality testing was conducted using hydrogen sulphide test and R2A based heterotrophic plate count. Raw water supplying Manyame River and tap water in Harare households were assessed for microbial quality. Results and Discussion - Raw water sources were found to be contaminated by faecal matter. Household water sources had no faecal contamination, but tested positive for heterotrophic bacteria. The CFU/ml quantities obtained ranged from 1- 452 CFU/ml for all samples. The WHO guidelines for domestic water sources recommend that domestic water should have no coliforms/100 ml sample. Disaster management protocols were available in disaster prone areas such as the Matabeleland South Province. No guidelines were in place for monitoring microbial water quality as a disaster prevention method. Conclusion - The current state of treated water supplied by the Morton Jaffray Treatment Plant was found to be suitable for domestic use, but not sufficient to meet the Harare population’s needs. The need to push for legislature supporting microbial water quality monitoring was recognised. Initiating public / private partnerships in water distribution and water quality monitoring in Zimbabwe was encouraged.
- Full Text:
- Date Issued: 2017
Preparation and evaluation of captopril - ion exchange resin complexes
- Authors: Chikukwa, Mellisa Tafadzwa Ruramai
- Date: 2017
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/59146 , vital:27441
- Description: Restricted access-thesis embargoed for 2 years
- Full Text:
- Date Issued: 2017
Sorptive and microbial properties of low-cost adsorbents used in the extraction of ciprofloxacin and isoniazid from aqueous solution
- Authors: Dube, Cyril Simbarashe
- Date: 2017
- Language: English
- Type: text , Thesis , Masters , MSC
- Identifier: http://hdl.handle.net/10962/59178 , vital:27450
- Description: This work describes how coal fly ash (FA), kaolinite, perlite, talc and vermiculite were used to remove ciprofloxacin and isoniazid from aqueous solutions. The adsorptive features of the adsorbents were evaluated for ciprofloxacin and isoniazid with regards to the effects of contact time, pH, solid/liquid ratio and antibiotic concentration. All adsorbents were sterilised by dry heat before use to avoid the proliferation of antimicrobial resistance by the bacteria present on the adsorbents during experiments. The regression correlation coefficients indicate that the linearised form of the Langmuir isotherm gives the best fit for the sorption of both antibiotics onto FA and talc, ciprofloxacin onto kaolinite, and isoniazid onto perlite and vermiculite with R2 values ranging from 0.908 - 0.999. The linearised form of the Freundlich isotherm best describes the sorption of ciprofloxacin onto vermiculite and isoniazid onto kaolinite with R2 values of 0.999 for both. The linearised form of the Temkin isotherm best describes the sorption of ciprofloxacin onto perlite with an R2 = 0.997. The values of the Freundlich exponent, 1/n, range from 0.221 - 0.998, indicating a favourable adsorption of ciprofloxacin and isoniazid onto the adsorbents. The heat of sorption, B, calculated from the Temkin plots has values ranging from 0.018 - 10.460 J/mol, indicating a physical adsorption process (physisorption). Adsorption equilibrium on all adsorbents was achieved after 30 min for both antibiotics and the kinetic data obtained conforms best to the pseudo-second order equation with R2 values ranging from 0.998 - 0.999. The removal of ciprofloxacin and isoniazid by all adsorbents except FA was strongly influenced by the pH suggesting that electrostatic interactions play a major role in the adsorption processes. All adsorbents except FA removed showed excellent adsorption of ciprofloxacin from aqueous solutions with all of them achieving removals ranging from 80 - 99%. The adsorbents were less efficient in removing isoniazid and kaolinite gave the highest removal of 55 %. Furthermore, the microbial quality of the adsorbents was investigated and the results revealed that kaolinite, talc, perlite and vermiculite were heavily contaminated with microorganisms. FA was sterile. The fungi isolated from the mineral adsorbents were in concentrations ranging from 2.13 x 106 to 1.25 x 107 CFU/g and were mostly moulds; Penicillium spp., Aspergillus niger, Aspergillus fumigatus, Aspergillus flavus, Cladosporium spp. and Rhizopus oryzae. One yeast was isolated and was identified as Candida albicans. The bacteria identified were in concentrations ranging from 4.96 x 106 - 1.19 x 109 CFU/g. E. coli, Enterobacter cloacae, Exiguobacterium spp., Pseudomonas aeruginosa, Bacillus spp. and Serratia liquefaciens. The leachability index (LI) values obtained for adsorbents indicated that it is highly unlikely that microorganisms could be leached out of the adsorbents by rain. Heat inactivation of the microorganisms at a 105 °C was totally unsuccessful. However, it was established that a dry heat dose of 160 °C for at least 15 min was sufficient to eradicate all microorganisms present in the adsorbents. The D-values for coliform bacteria from all samples were very similar ranging from 1.7-2.2 min indicating homogeneity in heat resistance by the microorganisms. The Pseudomonas aureginosa isolated had a D-value of 2.2 min. The fungi isolated from the samples had D-values ranging from 2.1-3.2 min.
- Full Text:
- Date Issued: 2017
Taste masking of clarithromycin with ion exchange resins
- Authors: Ntemi, Pascal Vitalis
- Date: 2017
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/65178 , vital:28701
- Description: Expected release date-May 2019
- Full Text:
- Date Issued: 2017
The development, manufacture and characterisation of niosomes intended to deliver nevirapine to the brain
- Authors: Witika, Bwalya Angel
- Date: 2017
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/65257 , vital:28715
- Description: Expected release date-May 2019
- Full Text:
- Date Issued: 2017
Gradient high performance liquid chromatographic method for the simultaneous analysis of efavirenz, emtricitabine and tenofovir
- Authors: Koekemoer, Sonya Mariana
- Date: 2016
- Language: English
- Type: text , Thesis , Masters , MPharm
- Identifier: http://hdl.handle.net/10962/54679 , vital:26599
- Description: In 2014, approximately 6.8 million people in South Africa were HIV-positive, and the majority of those affected are aged 15 or older. A fixed-dose combination (FDC) antiretroviral (ARV) dosage form containing one non-nucleotide reverse transcriptase inhibitor (efavirenz) and two nucleotide reverse transcriptase inhibitors (emtricitabine and tenofovir) was licensed in South Africa in April 2013. New consolidated guidelines for HIV management and prevention of mother to child transmission (PMTCT) were published by the South African Department of Health in December 2014 and the FDC is now the recommended first-line treatment for HIV-positive patients. According to these guidelines all such people aged 15 and older, and weighing more than 40 kg, with a CD4 count of ≤ 500/ μl will be eligible for antiretroviral therapy (ART) using the FDC. In addition every pregnant and breastfeeding woman is eligible for lifelong ART regardless of CD4 count and EFV can be used as first-line treatment for pregnant women regardless of the length of gestation state of the pregnancy at that time. The use of this simplified regime is likely to promote much needed and improved adherence to therapy. An investigation into the development of a stability-indicating reversed-phase high performance liquid chromatography (RP-HPLC) method for the simultaneous quantitation of EFV, FTC and TNF was undertaken. Isocratic HPLC analysis was found to be unsuitable due to the highly polar FTC molecule eluting in the void. Therefore a gradient HPLC method was developed and validated. The method was validated according to the International Conference on Harmonisation, now known as International Council for Harmonization (ICH). Correlation coefficients > 0.999 were obtained for each assessment of linearity and FTC, TNF and EFV are linear in the range 0.4-40 μg/ml, 0.6-60 μg/ml and 1.2-120 μg/ml. The equation of the best-fit least squares regression lines for FTC, TNF and EFV were y = 0.0191x+0.0007, y = 0.0163x+0.0116 and y = 0.01x+0.016, respectively. The method is accurate as the y-intercept was < 2% of the detector response for all ARV, and the method is precise in terms of intra- and inter-assay precision as all % RSD < 2%. The stability-indicating nature of the method was demonstrated under acidic, alkaline and oxidative stress in addition to UV exposure and elevated temperatures, and the individual chromatograms were overlaid using Empower® 3 Software to establish whether there was interference with the peaks of interest. The forced degradation studies demonstrated the selectivity of the method for the ARV compounds. The method was applied to assay and in vitro dissolution studies of commercially available tablets. The amount of each active ingredient released from Atripla® was determined and compared to the amount of each drug released from Aspen Efavirenz® and Truvada® (a combination of FTC and TNF). The percent FTC released from Atripla® and Truvada® was similar based on the acceptance criteria for immediate-release BCS class 1 compounds. Statistical analysis was undertaken to compare the dissolution profiles of FTC, TNF and EFV. The percent of these compounds released in these studies indicate that bioequivalence testing would be required to declare these products interchangeable. The validated RP-HPLC and in vitro dissolution test method are suitable for routine quality control testing of solid oral dosage forms containing EFV, FTC and TNF, and as the dissolution method can discriminate between different formulations of the same molecule, these tools can also be used for analysis during formulation development studies. The method is not suitable for the analysis of the ARV plasma due to lack of sensitivity and an inability to quantitate the compounds at the required concentration levels. The use of HPLC with mass spectroscopy for quantitation would enhance the sensitivity of the method and may eliminate the quantitation of the molecules in the presence of interference that was observed when using UV detection. Fixed dose combination tablets are convenient for patient therapy and it is likely that in the future more molecules will be formulated into such dosage forms. However formulations such as these can pose significant difficulties when developing and using analytical methods for the quantitation of all compounds in the dosage form at the same time, in particular when the compounds have vastly different physico-chemical properties that impact the quality of a separation and therefore the analysis. Therefore when embarking on the development of FDC product cognisance of the difficulties of developing single methods for the analyses is required and approaches to overcome these difficulties should be considered.
- Full Text:
- Date Issued: 2016
Investigation of α-aryl substituted 3-indolylethanones as potential antiplasmodial agents
- Authors: Svogie, Archibald Lesley
- Date: 2016
- Language: English
- Type: text , Thesis , Masters , MPharm
- Identifier: http://hdl.handle.net/10962/55487 , vital:26704
- Description: According to the World Health Organisation (WHO), deaths attributed to Plasmodium falciparum exceeded 584 000 in 2013, with 198 million new cases of malaria being reported. One contributing factor to these alarming figures is the emergence of drug resistance against available antimalarial agents. Therefore, there is a pressing need to develop new therapeutic antimalarial drugs with novel mechanisms of action in order to curb the increasing spread of malaria. The indole scaffold is often associated with biologically active compounds, recently exemplified by the antimalarial agent NITD609, which is currently in phase 1 clinical trials. Based on the biological evaluation of a small series of indolyl-3-amides and esters which showed moderate antimalarial activity, coupled to significant toxicity, we were prompted to investigate the synthesis of a series of indolyl-3-ethanone-α-amines (3.37 and 3.41), ethers (3.39 and 3.44) and thioethers (3.42, 3.43, 3.40, 3.45 – 3.73), where the carbonyl moiety and respective heteroatom were separated by a methine spacer. We further investigated these compounds for in vitro biological activity against P. falciparum and a human HeLa cell line. Our study explored the synthetic pathway of a three-step procedure toward our target compounds, with the initial Friedel-Crafts acetylation of indole, followed by α-bromination of the respective 3-acetylindoles. Finally, the halogen of the α-bromo ketone was substituted with an appropriate nucleophile, to yield our desired compounds. Various reagents were explored to optimise the nucleophilic displacement step, including potassium carbonate and various silver containing compounds. While many of the silver salts were found to assist in nucleophilic substitution, none were superior to the addition of potassium carbonate. The majority of compounds, chiefly the thioethers, displayed promising antimalarial activity, against the chloroquine sensitive 3D7 P. falciparum strain, with two thioethers in particular (3.54 and 3.65) inhibiting P. falciparum in the low nanomolar range. Additionally, active compounds were generally found to be non-toxic against HeLa cells, indicating that indolyl-3-thioethers are selective for the malaria parasite. These findings allowed us to begin hypothesising a structure activity relationship of this class, as well as elucidating the possible pharmacophore. In a speculative attempt to uncover the possible mechanism of action of these active compounds, in silico docking studies were conducted against Staphylococcus aureus HPPK (PDB ID: 4CRJ), which is an enzyme that immediately precedes DHPS in the microbial folate biosynthesis. Inhibition of folate biosynthesis is a validated selective antimalarial pathway and HPPK also exists in P. falciparum. Results from these docking studies suggested that our inhibitors bound well in the HPPK ATP pocket and were supportive of our hypothesized structure activity relationship.
- Full Text:
- Date Issued: 2016
Isolation, characterization and biomimetic oxidation of selected marine natural products and their analogues
- Authors: Mutsvairo, Tafadzwa
- Date: 2016
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/64685 , vital:28592
- Description: Marine brown algae produce a variety of terpenes with a wide range of biological activities. However, very few phytochemical studies of brown algae have been conducted in South Africa. Therefore, in our continued search for biologically active natural products, we examined the South African brown alga Brassicophycus brassicaeformis. The dichloromethane-methanol extract of B.brassicaeformis was fractionated by silica gel column chromatography followed by normal phase HPLC to give pure four pure compounds which were identified by spectroscopic methods as; fucosterol, fucoxanthin and two monogalactosyldiacylglycerol lipids. Many potential drug molecules such as natural products have failed to reach the market due to poor pharmacokinetic and metabolic profiles despite having potent biological activity. Therefore the importance of early drug metabolism studies in the drug development process is clear. A biomimetic oxidation model was used for in vitro drug metabolism studies to predict any possible metabolites that could be produced by these natural products. Two biomimetic oxidation models catalyzed by two water soluble metalloporphyrins as biomimics of cytochrome P450, in the presence of two terminal oxidants either hydrogen peroxide or iodobenzene diacetete were successfully developed. The models were applied to a range of natural products. The oxidation of the quinone natural products, sargahydroquinoic acid, and lapachol was most easily achieved by metalloporphyrins employed in this study.
- Full Text:
- Date Issued: 2016
Synthesis and biological evaluation of novel thiazole-based compounds
- Authors: Olawode, Emmanual Oladayo
- Date: 2016
- Language: English
- Type: text , Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/62955 , vital:28325
- Description: Thesis embargoed for one-year period. Expected date of release: April 2019
- Full Text:
- Date Issued: 2016
The development of captopril pellets using the principles of quality by design
- Authors: Veerubhotla, Hari Mani Krishna
- Date: 2016
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/64769 , vital:28599
- Description: Expected release date-May 2018
- Full Text:
- Date Issued: 2016
An investigation into the feasibility of incorporating ketoconazole into solid lipid microparticles
- Authors: Jhundoo, Henusha Devi
- Date: 2015
- Language: English
- Type: text , Thesis , Masters , MPharm
- Identifier: http://hdl.handle.net/10962/54701 , vital:26601
- Description: One of the major challenges of the oral administration of ketoconazole (KTZ), an inhibitor of sterol 14α demethylase, used in the management of systemic and topical mycoses in immuno-compromised and paediatric patients is the lack of availability of liquid dosage forms. In order to overcome this challenge, extemporaneous preparations have been manufactured by care-givers and health care providers by crushing or breaking solid oral dosage forms of KTZ and mixing with a vehicle to produce a liquid dosage form that can be swallowed by patients. However, the use of extemporaneous preparations may lead to under or over-dosing if the care-givers are not guided accordingly. Furthermore, the dearth of information on the stability of these KTZ-containing extemporaneous preparations may lead to ineffective antifungal therapy and complicate the problems of resistance as it is difficult to estimate the shelf-lives of these extemporaneous products under varying storage conditions due to the susceptibility of KTZ to chemical degradation. Therefore, there is a need for formulation scientists to develop novel drug delivery systems that avoid the need for extemporaneous preparations, possess well-established limits of stability and minimize the risks of systemic adverse effects to facilitate KTZ therapy. The use of solid lipid microparticles (SLM) as potential carriers for the oral administration of KTZ was investigated since solid lipid carriers are known to exhibit the advantages of traditional colloidal carriers. The research undertaken in these studies aimed to investigate the feasibility of developing and manufacturing solid lipid microparticles (SLM), using a simple micro-emulsion technique, as a carrier for KTZ. Prior to pre-formulation, formulation development and optimization studies of KTZ-loaded SLM, it was necessary to develop and validate an analytical method for the in vitro quantitation and characterization of KTZ in aqueous dispersions of SLM during development and assessment studies. An accurate, precise, specific and sensitive reversed-phase high performance liquid chromatographic (RP-HPLC) method coupled with UV detection at 206 nm was developed, optimized and validated for the analysis of KTZ in formulations. Formulation development studies were preceded by solubility studies of KTZ in different lipids. Labrafil® M2130 CS was found to exhibit the best solubilising potential for KTZ. Pre-formulation studies were also designed to determine the polymorphic behavior and the crystallinity of KTZ and Labrafil® M2130 CS that was used for subsequent manufacture of the solid lipid carriers. DSC and FTIR studies revealed that there were no changes in the crystallinity of KTZ or Labrafil® M2130 CS following exposure to a temperature of 60°C for 1 hour. In addition the potential for physicochemical interaction of KTZ with the lipid Labrafil® M2130 CS was investigated using DSC and FTIR and the results revealed that KTZ was molecularly dispersed in Labrafil® M2130 CS and that it is unlikely that KTZ would interact with the lipid. It was therefore established that KTZ and Labrafil® M2130 CS were thermo-stable at a temperature of 60°C and thus a micro-emulsion technique could be used to manufacture the KTZ-loaded SLM. Drug-free and KTZ-loaded SLM were prepared using a modified micro-emulsion technique that required the use of an Ultra-Turrax® homogenizer set at 24 000 rpm for 5 minutes followed by the use of the Erweka GmbH homogenizer. SLM were characterized in terms of particle size (PS), zeta potential (ZP), shape and surface morphology using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). In addition drug loading capacity (DLC) and encapsulation efficiency (EE) of SLM for KTZ were assessed using RP-HPLC. Formulation development and optimization studies of KTZ-loaded SLM were initially aimed at selecting an emulsifying system that was able to stabilize the SLM in an aqueous dispersion. Successful formulations were selected based on their ability to remain physically stable on the day of manufacture. Pluronic® F68 used in combination with Lutrol® E40, Soluphor® P, Soluplus® produced unstable dispersions on the day of manufacture and these combinations were not investigated further. However, the formulation of a stable KTZ-loaded SLM dispersion was accomplished by use of a combination of Pluronic® F68, Tween 80 and sodium cholate as the surfactant system. Increasing amounts of Labrafil® M2130 CS resulted in the production of particles with low DLC and EE, a large PS and a relatively unchanged ZP. An optimum concentration of 10% w/v Labrafil® M2130 CS was selected to manufacture the KTZ-loaded SLM. Studies to determine the influence of KTZ loading on the quality of SLM revealed that concentrations of KTZ > 5% w/v led to a reduction in DLC and EE and an increase in PS with minimal impact on the ZP. Stability studies conducted at 25°C/65% RH and 40°C/75% RH for up to 30 days following manufacture revealed that batch SLM 15 manufactured using 10% w/v Labrafil® M2130 CS, 5% w/v KTZ and a combination of 4% w/v Pluronic® F-68, 2% w/v Tween 80 and 1% w/v sodium cholate produced the most stable dosage form when stored at 25°C/65% RH for up to 30 days. However, storage at 40°C/75% RH resulted in instability of the formulation. An aqueous dispersion of KTZ-loaded SLM has been developed and assessed and may offer an alternative to extemporaneous preparations used for KTZ therapy in paediatric and immuno-compromised patients.
- Full Text:
- Date Issued: 2015
Development and manufacture of sustained release captopril beads
- Authors: Mhaka, Farai Arthur
- Date: 2015
- Language: English
- Type: text , Thesis , Masters , MPharm
- Identifier: http://hdl.handle.net/10962/54712 , vital:26602
- Description: Hypertension has a high mortality rate in developing countries such as South Africa. Although the prevention and control of hypertension is a health priority, efforts to decrease the global burden of hypertension and improve control over the condition are inadequate. The use of angiotensin converting enzyme (ACE) inhibitors such as captopril (CPT) have been effective for the management of hypertension when used as first line therapy alone or in combination. Commercially available immediate release dosage forms containing 12.5, 25 and 50 mg of CPT are administered two or three times a day to treat hypertension. CPT degrades in aqueous media with the sulfhydryl functional moiety responsible for adverse effects such as hypersensitivity, taste disturbances and/or presenting with a dry hacking cough. CPT has a short elimination half-life of between 1.6 and 1.9 hours, which means that the compound is a suitable candidate for inclusion in sustained release (SR) dosage forms. Manufacturing a SR dosage form of coated beads for twice daily dosing may reduce the incidence and intensity of undesirable adverse effects, improve the stability of CPT and improve patient adherence. A stability indicating reversed-phase high performance liquid chromatographic (RP-HPLC) method was developed and optimised using a central composite design approach. As part of this approach the interactive effects of input factors, viz. pH, methanol (MeOH) content and column temperature on retention time, were investigated to achieve a separation with well-resolved and symmetrical peaks for CPT and salicylic acid. The method was validated using ICH guidelines and was found to be simple, linear, precise, accurate, selective and rapid for the in vitro quantitation of CPT. The method was successfully applied for the analysis of both commercially available and test formulations. Preformulation studies were undertaken to establish the physical and chemical properties of CPT, excipients and dosage forms to ensure the production of stabile and bioavailable products. Powder blends were assessed for flow properties using angle of repose (AOR), and bulk and tapped density, which were subsequently used to calculate Carr’s Index (CI) and the Hausner ratio (HR). The addition of talc resulted in the most powder blends with AOR, CI and HR that were within a range indicative of satisfactory to good flow properties. The use of talc was necessary to ensure that blending prior to wet granulation and extrusion-spheronisation would produce homogenous powders. Thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and Fourier Transform Infrared Spectroscopy (FT-IR) were used for the identification and purity of CPT alone and 1:1 binary mixtures with excipients in an effort to establish if CPT was likely to undergo physical and/or chemical modification during production. The DSC thermograms for all CPT-excipient mixtures revealed the presence of a melting endotherm that was wider, occurring at 110.93 °C (Tpeak for pure CPT). The characteristic peaks for specific functional groups were present in the FT-IR spectra for powder mixtures, indicating the absence of incompatibilities. Dialysis studies were used to investigate if the ammonium oleate present in Surelease® E-7-19010 interacted with CPT. The results suggests that an interaction between CPT and Surelease® E-7-19010 during processing of CPT beads was unlikely to occur. Preliminary investigations reveal that Methocel® K100M, Methocel® E4M, Avicel® PH102, Eudragit® RS PO, Surelease® E-7-19010 and talc are compatible with CPT and could be used for the manufacture of SR CPT beads. CPT beads were manufactured using extrusion-spheronisation and coated using a fluidised bed drier fitted with a Wurster insert. The amount of granulating fluid, coating levels, curing time and formulation composition were varied to achieve CPT release with specific criteria to develop a preliminary formulation. The coated beads met all desired quality attributes in respect of micromeritic and flow properties, content uniformity and friability. Response Surface Methodology was used to further optimise the SR CPT formulation. The Plackett-Burman design was used for this process to produce an SR dosage form with desirable quality attributes achieved by altering formulation composition, extrusion-spheronisation variables and coating parameters. ANOVA data revealed significant responses for yield, aspect ratio, sphericity, coating efficiency and cumulative percent CPT released at 2 and 12 hours. Formulations in which the high molecular weight HPMC were used in increased concentrations resulted in the formation of a sticky wet mass and extrudate, resulting in a decrease in yield. The application of a permeable, but insoluble Surelease® coat onto the surface of the beads formed a barrier that complements the activity of the hydrophilic matrix in preventing rapid dissolution and retarding the release of CPT from the beads. The amount of CPT released over 12 hours revealed that increasing the Methocel® K100M content entrapped CPT and retained it more efficiently in the hydrated matrix, resulting in a slow rate of CPT release. In vitro release data were fitted to a number of models in an attempt to elucidate mechanistic aspects of transport processes specific to CPT from the coated bead formulations. The results of fitting data from optimised batches revealed that the goodness of fit based on the adjusted correlation coefficient ranged between 0.953 and 0.976 for the Higuchi model, indicating that diffusion is a predominant factor that controls CPT release from the coated beads. The results of fitting data to the Korsmeyer-Peppas model suggest that the mechanism of CPT release includes transport of the dissolution medium from the vessel reservoir into the core of the bead due to osmotic potential, dissolution of CPT, mass transfer of the dissolved CPT within the core, partitioning between the solution and polymeric film, mass transfer of dissolved CPT through the film to ultimately reach the bulk dissolution fluid. A SR CPT bead formulation that has potential for further development and optimisation for scaled-up production using RSM approaches and Design of Experiments such as CCD or Box-Behnken has been successfully developed and manufactured using extrusion, spheronisation and coating processes. Assessment of all batches of beads manufactured exhibited satisfactory to good flow properties and demonstrated SR profiles over 12 hours that met USP criteria for SR dosage forms.
- Full Text:
- Date Issued: 2015
Formulation, development and assessment of tenofovir disoproxil fumarate-loaded pellets
- Authors: Dube, Tawanda
- Date: 2015
- Language: English
- Type: text , Thesis , Masters , MPharm
- Identifier: http://hdl.handle.net/10962/54690 , vital:26600
- Description: Tenofovir disoproxil fumarate (TDF) is a novel nucleotide analog reverse transcriptase inhibitor that is recommended by the WHO for use in first line treatment of HIV infections. Due to the high dose of TDF for anti-retroviral treatment the formulation of a pellet dosage form may improve patient adherence by incorporation of a large dose in a relatively small dosage form. TDF is currently only available in tablet form. A simple, sensitive, selective, rapid, accurate, precise, stability indicating reversed-phase HPLC method was developed and validated in accordance with ICH guidelines and was successfully used for the analysis of TDF raw material and pharmaceutical dosage forms. Preformulation studies included an investigation of TDF-excipient and excipient-excipient interactions with all materials that could potentially be used to produce extruded and spheronized pellets. Nuclear Magnetic Resonance spectroscopy (NMR), Infrared Spectroscopy (IR), Differential Scanning Colorimetry (DSC) and Thermogravimetric analysis were used for identification and purity testing of TDF and all excipients. DSC data revealed that no potential interactions between TDF and the excipients occurred suggesting that incompatibility reactions were unlikely during manufacture and storage. These findings were confirmed by IR analysis that revealed that no physical interaction was likely between any of the excipients used and TDF. DSC data also reveal the existence of the α and β-polymorphs of TDF as evidenced by two enthalpy changes observed on the resultant thermograms. The existence of two polymorphs is unlikely to result in incompatibility and was confirmed by IR analysis. The IR spectra reveal that all characteristic peaks for TDF were present in 1:1 binary mixtures. Therefore TDF is compatible with all excipients tested and thermal analysis confirmed the stability of TDF under manufacturing conditions. The temperature of degradation temperature established through DSC analysis confirmed that degradation during manufacture is unlikely as the temperature of manufacture is lower than that at which degradation occurs. Extrusion and spheronization were the processes used to manufacture TDF pellets as it is a simple and economic approach for production. The effects of extruder and spheronizer speed, amount of spheronization aid and diluents on the pellet size, shape, flow properties and TDF release characteristics were examined. In order to decrease the complexity of analysis and reduce the cost of development a Taguchi orthogonal array design of experiments was successfully applied to evaluate the impact of formulation variables on product characteristics and predict an optimized formulation with a minimum number of experiments. The use of Response Surface Methodology for the development and optimization of pharmaceutical systems, including the optimization of formulation composition, manufacturing processes and/or analytical methods is well established. However the application of RSM requires that accurate, precise and reproducible experimental conditions are used for the generation of reliable data and RSM use is limited due to sensitivity to experimental variability. The benefits of using RSM for formulation optimization include the fact that more than one variable can be investigated at a time and large amounts of information can be generated at the same time ensuring a more efficient process with respect to time and cost. An added advantage of this approach is that mathematical relationships can be generated for the models that are produced and provide formulation scientists with an indication of whether the effect(s) between factors are synergistic or antagonistic. There are several statistical design approaches that use RSM and a Taguchi orthogonal array design was selected for use in this optimization process as fewer experiments are required to generate data for the same number of factors to be investigated when compared to other statistical designs such as Central Composite (CCD) and Box-Behnken designs. The use of RSM clearly demonstrates the impact of different input variables on the % TDF released at 45 min and % TDF loaded into the particles. The amount of sorbitol and Kollidon® CL-M were the only significant variables that affected the % TDF released at 45 min and both excipients had an overall synergistic effect on the in vitro release of TDF. The prediction and manufacture of an optimized formulation led to the production of pellets that met predetermined specifications which was successfully achieved using RSM. The development of a TDF containing pellet dosage form has been achieved and the formulation, manufacture and characterization of the dosage form reveal that the product has the potential to be further developed.
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- Date Issued: 2015
Isolation and structure elucidation of halogenated metabolites from Portieria hornemannii and Portieria tripinnata
- Authors: Adam, Mohammed
- Date: 2015
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/64674 , vital:28591
- Description: The red marine algal genus, Portieria, is known to produce a number of potent cytotoxic compounds with anticancer potential. The most important anticancer lead produced by this genus is the compound halomon. Unfortunately, the lack of sufficient quantities of this compound hampered its further development. Two Portieria species, Portieria hornemannii and Portieria tripinnata, are found along the South African coastline. Recent studies, based on DNA analysis, suggest that Portieria hornemannii may in fact be divided into several cryptic species. The current project is part of a larger study designed to investigate the use of secondary metabolites to identify new marine algal species. In this study 1H NMR profiles of the organic extracts of selected Portieria spp were compared in order to identify new species. Selected compounds were then isolated and characterised as potential chemotaxonomic markers. Four halogenated monoterpenes were isolated from Portieria hornemannii. Two of these were new compounds 4-(3-bromo-4-chloro-4-methylpentyl)-3-chlorofuran-2(5H)-one, which were isomers of each other. The two known compounds had been previously isolated from Portieria hornemannii samples off the Madagascar coast. These compounds could prove to be useful as chemotaxonomic marker compounds, as they have never been isolated from any other species of marine algae. Three known halogenated monoterpenes were isolated from Portieria tripinnata. These compounds had been previously isolated from different species of marine algae and therefore, could not serve as chemotaxonomic marker compounds for this species of marine alga. Further work needs to be done on Portieria tripinnata, with regards to its chemistry, as it is a species of marine algae that has not been previously researched.
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- Date Issued: 2015