There are mainly two manufacturing processes used in the pharmaceutical industry, namely direct compression and granulation of which granulation can be subdivided into wet granulation and dry granulation. Wet granulation is a process still widely used in the pharmaceutical industry and provides better control of drug content uniformity and compactibility at low drug concentrations. Lactose monohydrate and microcrystalline cellulose (MCC) were used as fillers in this study. Both these fillers possess unacceptable powder flow properties and the use of wet granulation may improve this property. One of the advantages of lactose monohydrate over MCC is that it is partially water soluble. A fractional factorial design was used in this study. Twelve tablet formulations were formulated containing different combinations of active ingredients (furosemide or pyridoxine hydrochloride), fillers (lactose monohydrate or MCC) and a binder (Kollidon® VA64) in three different concentrations (0.75, 1.5 or 3.0% w/w). The binder was used to produce granules by means of wet granulation, using ethanol as granulating fluid. The granules were dried in an oven and screened through different sized sieves to produce the final granulated powder formulations ready for tableting. A disintegrant (Ac-di-sol®) and lubricant (magnesium stearate) were incorporated into the granulated powder formulations extra-granular (0.5% w/w) and were kept as a constant in this study throughout all the formulations. A Turbula® mixer was used to mix the granulated powder formulations for a constant 5 minutes. During the first phase of the study, tablets were compressed using 2 compression settings (22 and 24). These compression settings were used to determine what effect different external pressures would have on the different tablet properties. Tablet weight for all the formulations was kept constant at 250 mg, although the volume of the matrix differed for each tablet formulation. The physical properties of the tablets were evaluated with regard to weight variation, mechanical strength (crushing strength and friability) and disintegration. Tablet formulation 12 yielded unsatisfactory tablets, due to poor powder flow into the die. Tablet formulations that contained the highest binder concentration (3.0% w/w) and were compressed at the highest compression setting (24) (formulations 4 and 9), exhibited the highest mechanical strength. The disintegration results revealed that the tablet formulations containing MCC as filler disintegrated faster compared to those containing lactose monohydrate. The increase in binder concentration caused an increase in mechanical strength, possibly decreasing tablet porosity, therefore prolonging disintegration time due to impeded water penetration into the tablet matrix. During the final phase of the study, dissolution studies were conducted on the different tablet formulations in 0.1 M HCl for 120 minutes. In terms of dissolution results, the initial dissolution rate (DRi) and extent of dissolution (AUC) were compared. It was found that the tablet formulations containing pyridoxine hydrochloride as active pharmaceutical ingredient (API) exhibited faster drug dissolution (higher DRi and AUC-values) compared to those tablet formulations containing furosemide. The faster dissolution exhibited by the pyridoxine hydro- chloride containing formulations can possibly be attributed to the fact that pyridoxine hydrochloride is good water soluble whereas furosemide is practically insoluble in water. The effect of the filler depended on the aqueous solubility of the filler and the concentration of the binder (Kollidon VA64) employed. An increase in binder concentration led to a decrease in the initial rate of dissolution as well as the extent of drug dissolution. In the case of the pyridoxine hydrochloride containing formulations, formulation 9 exhibited the slowest DRi and lowest extent of drug dissolution (1.40 ± 0.03 µg.cm-3.min-1 and 2396.52 ± 26.43 µg.cm-3.min respectively). In the case of the furosemide containing formulations, formulation 4 exhibited the slowest DRi and lowest extent of drug dissolution (0.22 ± 0.07 µg.cm-3.min-1 and 1018.62 ± 59.74 µg.cm-3 min respectively). In both cases, the formulations contained Kollidon VA64 in a concentration of 3% w/w and were compressed at compression setting 24. The disintegration process of tablets goes hand in hand with the dissolution process and results have shown that by establishing rapid contact between drug particles and the surrounding medium proves to be a necessity for rapid drug dissolution. Disintegration does not assure drug dissolution, but when prolonged, slower dissolution rates can be obtained, implying a slow rate and low extent of drug dissolution. The disintegrant in this study was incorporated extra-granular ensuring rapid tablet disintegration. However, due to binder concentration of 3% w/w, granule disintegration was probably negatively affected resulting in a lower drug surface area exposed to the surrounding dissolution medium, leading to a slower initial rate and extent of drug dissolution. From the results obtained during this study it was evident that formulation variables such as the type of filler, the concentration of the binder and compression setting employed during tablet manufacturing can have a ronounced effect on the pharmaceutical availability of the active ingredient. However, the extent of the effect was dependent on the aqueous solubility of the active ingredient. / Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013.

Objectives: To review, develop, and validate appropriate methods for quality control testing of sublingual (SL) tablets; to formulate and characterize new generations of SL tablets of epinephrine (E) for the potential first-aid treatment of anaphylaxis; and to evaluate the effects of non-medicinal ingredients (NMIs) on the in vitro characteristics and in vivo bioavailability of the formulated tablets. Methods: A custom-made apparatus and a novel method that simulates SL conditions were evaluated for dissolution testing of SL tablets. An electronic tongue (e-Tongue) was used to assess the degree of E bitterness and to demonstrate the masking effects of sweetening and/or flavoring agents. The effect of several NMIs in various properties on the in vitro characteristics of new generations of E SL tablets was evaluated. Formulations with the best in vitro characteristics, containing E 30 mg and 40 mg, were evaluated in vivo using our validated rabbit model and compared with placebo SL tablets (negative control) and E 0.3 mg intramuscular (IM) injection (positive control). Results: The novel in vitro dissolution testing resulted in accurate and reproducible data and was capable of detecting the effect of minor changes in formulations. Using the e-Tongue, E bitartrate had an extremely bitter taste which was masked to various degrees by the addition of aspartame, acesulfame potassium, and citric acid alone or in combination. Citric acid alone masked the bitter taste by >80%. The evaluation of NMIs revealed that the best formulation contained specific proportions of mannitol and coarse and fine grades of microcrystalline cellulose. Appropriate comparative testing resulted in the selection of a taste-masked E SL formulation with optimum in vitro characteristics. This formulation containing E 40 mg resulted in similar bioavailability to E 0.3 mg IM. This formulation containing E 30 mg had higher bioavailability than placebo, but lower bioavailability than E 40 mg tablets. Conclusions: Grades and proportions of NMIs carefully selected using appropriate in vitro testing resulted in successful formulations. The results of these in vitro tests enabled the development of the optimum E SL tablet formulation which was bioequivalent to the EpiPen. These tablets are potentially suitable for Phase 1 studies in humans and might transform the first-aid treatment of anaphylaxis in community settings.

This dissertation includes three papers that address various aspects of the economics of labour and the family. The dissertation integrates the discussion on the following issues: (1) the allocation of housework and childcare in Canadian two-earner households (2) the effect of family policy reform on time allocation and labour supply in two-parent families (3) effect of anticipated divorce and divorce duration on male and female labour supply. The first paper Time Allocation Gender Gap in Native-born and Foreign-born Families in Canada focuses on the difference between the housework and childcare share produced by foreign-born husbands compared to Canadian-born husbands. This empirical analysis employs the data from the Canadian General Social Survey. The results show that foreign-born husbands have a lower share of housework and childcare compared to their Canadian-born counterparts. The second paper The effect of Quebec childcare policy change on the labour market outcomes and time distribution in the family analyzes the effect of the childcare policy change that took place in Quebec in 1997-2000. The results show that the introduction of “$5 per day” daycare subsidized by the Quebec government increased the labour supply of married mothers and also affected the allocation of time husbands and wives spend on housework and childcare. The data from this project were drawn from 1996 and 2001 Canadian Census. The third paper Labour supply of Australian men and women before and after divorce studies the changes in the labour supply of men and women before and after divorce. The data for empirical analysis employs 12 waves of Household, Income and Labour Dynamics in Australia Survey (HILDA). The outcome suggests that men and women do not change labour participation and weekly working hours in anticipation of divorce. Women increase labour force participation and weekly hours worked as a result of divorce. Men’s labour supply does not change in response to divorce.

The ultimate goal of this study is to examine the feasibility of extracting silicon from silica through electrolysis. The objective of the thesis was to evaluate the physico-chemical properties of a cryolite-lithium fluoride mixture as an electrolyte for the electrolysis process. A study of 86.2wt%Cryolite and13.8wt%Lithium fluoride melt with silica concentration varying from 0-4wt% and temperature range of 900-1000°C was done. Three properties were measured using two sets of experiments: 1) Dissolution Behaviour Determination, to obtain a) solubility limit, b) dissolution rate (mass transfer coefficient) and 2) density using Archimedes’ Principle. The study concluded that solubility and dissolution rate increases with temperature and the addition of LiF to cryolite decreases the solubility limit but increases the rate at which silica dissolves into the melt. With addition of silica, the apparent density of electrolyte first increases up to 2-3wt% and the drops.

The ultimate goal of this study is to examine the feasibility of extracting silicon from silica through electrolysis. The objective of the thesis was to evaluate the physico-chemical properties of a cryolite-lithium fluoride mixture as an electrolyte for the electrolysis process. A study of 86.2wt%Cryolite and13.8wt%Lithium fluoride melt with silica concentration varying from 0-4wt% and temperature range of 900-1000°C was done. Three properties were measured using two sets of experiments: 1) Dissolution Behaviour Determination, to obtain a) solubility limit, b) dissolution rate (mass transfer coefficient) and 2) density using Archimedes’ Principle. The study concluded that solubility and dissolution rate increases with temperature and the addition of LiF to cryolite decreases the solubility limit but increases the rate at which silica dissolves into the melt. With addition of silica, the apparent density of electrolyte first increases up to 2-3wt% and the drops.

Acid treatments have predominantly been conducted using HCl for its availability, high rock dissolving power and soluble reaction products. At high temperatures, rapid spending of the acid with carbonates prevents deeper penetration distance into the formations. Alternative fluids such as acetic and formic acid have lent themselves to retarded reaction rates, low corrosivity and reduced tendency to form acid/oil sludge in asphaltene-rich crudes but for high reaction rate problems. Chelating agents, with the added advantage of complexing with alkali-earth metals in carbonates to form water-soluble products that are thermally stable at high temperature, have been introduced as stimulation fluids. Glutamic acid diacetic acid (GLDA) ethylenediaminetetraacetic acid (EDTA) and hydroxyethylenediaminetriacetic acid (HEDTA) are aminopolycarboxylic acids that were studied. To predict the spending of chelating agents relative to simple organic acids at temperatures between 150 and 250˚F, the chemical kinetics of dolomite dissolution in these acid solutions were investigated over different reaction conditions in a rotating disk apparatus. Samples of the reacted acids from the reactor were collected and then analyzed with inductively coupled plasma (ICP). Analyses of the experimental data were carried out to determine kinetic parameters of the heterogeneous reactions needed for matrix stimulation of dolomitic reservoirs. Experimental results indicated that dolomite dissolution rates increased in all the acid solutions as the disk rotational speeds increased at 150, 200, and 250˚F. The dissolution of dolomite in 0.886 M GLDA was found to be surface-reaction limited at lower temperatures and mass-transfer limited at highest temperature. GLDA with the lowest reaction rates and relative diffusion coefficient demonstrated retardation before spending with deeper penetration capability for productivity and injectivity improvement.

Herewith are presented the results of an investigation the statistical power of USP compendial release tests and recommended alternatives. <br>The U.S. drug supply chain, formerly protected by a closed distribution network, is now threatened by the legal and illegal importation of drug products. Whereas quality can never be inspected into final products, compendial release standards may represent the only valid assessment that products of dubious origin would receive. Reliable tests for content uniformity and dissolution are required to protect the safety of the supply chain. A study was designed to test the hypothesis that existing compendial tests for content uniformity and dissolution would protect the supply chain against substandard and counterfeit drugs if basic field tests failed. <br>Compendial tests for content uniformity and dissolution were evaluated for statistical power using simulation studies. The results revealed that the revised content uniformity test, based on tolerance analysis, was subject to an unacceptable level of consumers' risk. The Bergum method proved to be an excellent secondary standard for product assessment and is recommended as an alternative to the USP method. Simulations with the USP dissolution test revealed significant weaknesses and inconsistencies in the test structure. Theoretical models and power assessments confirmed that the coverage specification of the dissolution test was an unacceptably high 50% coverage with 50% confidence. <br>A Bayesian D-optimal design program was used to investigate alternative methods to improve the coverage capability of the USP dissolution test. The result of this program was the identification of two alternatives to the existing USP procedure. The first alternative is based on the addition of attribute coverage tests to stages 2 and 3 of the USP test, whereas the second alternative is based on the concept of tolerance analysis. <br>Validation studies confirmed that both alternatives significantly improved the statistical power of the USP dissolution test without increasing the sample size or modifying the current three-stage procedure. The attribute test is non-parametric and behaves similarly to the existing USP with improved coverage, whereas the continuous alternative is more sensitive and is consistent with the recent revisions to the content uniformity test. / Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences / Pharmaceutics / PhD / Dissertation

Sodium hydroxide can cause cellulose to swell and can even dissolve cellulose in a narrow range of the phase diagram. It was found that for cellulose with low to moderate degree of polymerization, the maximal solubility occurs with 8~10% soda solution. In recent years, researchers found that sodium hydroxide with urea at cold temperature can dissolve cellulose better than sodium hydroxide alone. However, the lack of sufficient understanding of the NaOH and NaOH/urea dissolution process significantly constrains its applications. In order to fully understand the cellulose dissolution in alkali system, there are several aspects of problems that need to be addressed. Our focus in this study is in the interaction of cellulose with alkali solution at low temperatures, the improvement of its solubility, and the effect of hemicellulose and lignin.

Discontinuous planes often develop in soils; examples include shear bands, desiccation cracks, polygonal faults, and hydraulic fractures. These discontinuities affect the mechanical behavior (stiffness and strength) and transport properties of sediments (fluid migration and diffusion). Contrary to discontinuities in solid materials, granular materials such as soils are already separated at the particle scale. Therefore, the fundamental understanding of the development of discontinuities in soils must recognize their inherent granular nature and effective-stress dependent behavior. This research focuses on particle-scale mechanisms involved in contraction-driven shear failure due to mineral dissolution, desiccation cracks, and hydraulic fractures. Complementary experimental, analytical and numerical methods are used to study three cases. Contraction-driven polygonal fault formation under the seabed. Shear failure planes are often found in sediments that formed under near horizontal burial conditions. Particle-scale volume contraction due to mineral dissolution causes a decrease in the state of stress from the insitu K0-condition to the active failure Ka stress field. Shear strain localization follows in sediment with post-peak strain softening response. Desiccation cracks in saturated fine soils. The formation of desiccation cracks in soils is often interpreted in terms of tensile strength, which contradicts the cohesionless, effective stress dependent frictional behavior of fine grained soils. Experimental results monitored using high resolution time lapse photography point to a proper effective stress-dependent mechanism centered on the invasion of the air-water interface membrane. Miscible and immiscible fluid-driven fracture formation. Hydraulic fracture in granular materials cause grain separation and the development of conduits for preferential fluid flow leading to fracture formation due to the forced invasion of either immiscible or miscible fluids. Capillary, seepage, and skeletal interparticle forces define particle scale mechanisms at the fracture tip. Numerical simulations confirm that the effective stress remains in compression everywhere throughout the granular medium in the three localization mechanisms.

L'objectif principal de ce travail est de comprendre les phénomènes de dissolution sélective et de cartographier la dissolution sélective des alliages Zn-Al et des alliages Zn-Mg-Al dans une moindre mesure en fonction du pH et de potentiel. Cela aidera à construire un modèle prédictif de couplage galvanique qui est une préoccupation majeure de l'industrie automobile. Pour s'approcher de la cible, nous utilisons la spectroélectrochimie d'émission atomique (AESEC) qui est une combinaison de méthodes électrochimiques et analytiques. Cette technique nous permet de quantifier en temps réel et séparément les taux de dissolution de zinc et d'aluminium à partir des alliages Zn-Al au potentiel de circuit ouvert et du potentiel appliqué dans différentes solutions. Dissolution sélective de zinc et d'aluminium à partir des alliages Zn-Al est ensuite tracée dans les gammes du pH et de potentiel. Les explications relatives à la dissolution sélective et les phénomènes d'inhibition survenant au cours d'expériences sont également donnés grâce à des résultats complémentaires de certains autres méthodes de caractérisation de surface (DRX, MEB / EDS, IR et XPS).