<p>Agglomeration (the sticking together of particles) is often the major growth mechanism in granulation processes. The population balance equation (PBE) is a mathematical framework that is often applied to systems to describe how the particle size distribution changes as a function of time. Different kinetic terms are included in the PBE to describe the different particle growth mechanisms. In this work, a new kinetic model framework is proposed for the growth mechanism binary agglomeration. Binary agglomeration means that only two particles are involved in an agglomeration event. The generality of the new model framework is an advantage over the previous coalescence kernel framework. It is shown that an existing coalescence kernel model can be expressed by means of the new framework.</p><p>The new model framework is then adapted to the special case of fluidized bed granulation (FBG) by proposing/choosing expressions for the three submodels in the model framework. An advantage of the new FBG model is that a maximum number of agglomeration events per unit time can be estimated. This means that the model is one step closer to being used predictively. At the moment, no population balance models can predict granulation processes where agglomeration is the dominant growth mechanism. It is shown that both the new FBG model and an existing model could fit experimental data well, however, the new model reflects the situation that the presence of surface liquid is rate limiting for the agglomeratio process.</p><p>Experiments in a laboratory batch fluidized bed granulator were carried out. Samples of the particle size distribution were taken at intervals during an experiment. These data were used to fit the model parameters of the FBG model. The dissertation includes a discussion of the effect of certain operating conditions such as bed temperature and liquid spray rate on a model parameter.</p>

<p>Steam explosions are possible during granulation of Si and FeSi75. These explosions are a great hazard, and must be avoided. Norwegian ferroalloy producers have initiated a research program to learn more about such violent melt-water interactions, in a joint effort with NTNU and SINTEF. The focus has primarily been on important parameters that can be controlled industrially, such as water temperature and metal composition. This thesis-work has focused on the effect of small additions of Al and Ca in Si-metal and FeSi75. However, within the same project, experiments on the effect of water temperature have also been carried out.</p><p>The work has primarily been of experimental character. Two experimental apparatuses have been used. The first apparatus allows us to rapidly melt a sample of metal in an inert atmosphere to a desired temperature, expose the surface of the melt to an oxidizing agent (i.e. water) and then rapidly cool the sample to room temperature. The oxide that forms at the surface is examined with a microprobe. Thus, information regarding the composition and substance of the oxide layer is available. The second apparatus is suitable for releasing single drops of melt into a water tank, where they can be triggered and explode. A variety of techniques have been used in order to monitor the experiment: regular video, high-speed film, high-speed video, open-shutter imaging and pressure transducer measurements. </p><p>Both Si and FeSi75 must be triggered in order to explode. Trigger pressures range from 0.3 MPa (FeSi75) to 2 MPa (Si-metal). We have established at which depths the molten drops can be triggered. Molten drops of FeSi75 can be triggered at depths twice of those of molten drops of Si. The latter can be triggered even if they are partially solidified.</p><p>The explosion itself is strong enough to trigger neighbor drops as far away as 400 mm. Thus, we cannot rule out the possibility of large-scale steam explosions during granulation of molten Si or FeSi75, which is in accordance with industrial practice.</p><p>By the use of high-speed imaging techniques and pressure measurements, we have been able to describe qualitatively what happens when a molten drop of Si/FeSi75 fragments rapidly in water. As the melt fragments, the rapid heat transfer generates vapor as bubbles, which expand and collapse in a cyclic manner. Large pressure pulses are generated upon collapse of the steam bubble, that is, when water jets impact in the center of the collapsing bubble.</p><p>The first step in the oxidation of liquid silicon is the formation of gaseous SiO. The fate of this gas now depends on the flow conditions at the surface of the melt. In the case of a molten drop descending in water, most of the gas is flushed away from the surface. Thus, there are only minor traces of oxygencontaining material (i.e. silica) at the surface of the solidified drop.</p><p>The addition of small amounts of Al and/or Ca dramatically changes the behavior of the molten drop. A strange effect is the two-fold increase in the fall velocity for molten drops of silicon. A similar effect was detected for molten drops of FeSi75. Alloying elements such as Al and Ca greatly reduce the risk for a steam explosion of molten Si. The significance of these elements is related to the oxidation reactions at the surface of the molten drop of metal. As silicon reacts with water vapor and oxidizes, hydrogen gas is formed. If Al and Ca are present in the melt, these elements will speed up the hydrogen generation considerably. This gas is strongly influencing on the probability for a steam explosion to occur. H2 stabilizes the vapor film around the drop, that is, much stronger trigger pressures are needed to collapse the film. Even if the trigger pressure is strong enough to collapse the vapor film, violent interactions are almost completely absent. A fragmentation of the melt is observed, but the heat transfer is apparently not rapid enough to generate steam bubbles, i.e. the generation of steam is below the critical limit.</p>

Agglomeration (the sticking together of particles) is often the major growth mechanism in granulation processes. The population balance equation (PBE) is a mathematical framework that is often applied to systems to describe how the particle size distribution changes as a function of time. Different kinetic terms are included in the PBE to describe the different particle growth mechanisms. In this work, a new kinetic model framework is proposed for the growth mechanism binary agglomeration. Binary agglomeration means that only two particles are involved in an agglomeration event. The generality of the new model framework is an advantage over the previous coalescence kernel framework. It is shown that an existing coalescence kernel model can be expressed by means of the new framework. The new model framework is then adapted to the special case of fluidized bed granulation (FBG) by proposing/choosing expressions for the three submodels in the model framework. An advantage of the new FBG model is that a maximum number of agglomeration events per unit time can be estimated. This means that the model is one step closer to being used predictively. At the moment, no population balance models can predict granulation processes where agglomeration is the dominant growth mechanism. It is shown that both the new FBG model and an existing model could fit experimental data well, however, the new model reflects the situation that the presence of surface liquid is rate limiting for the agglomeratio process. Experiments in a laboratory batch fluidized bed granulator were carried out. Samples of the particle size distribution were taken at intervals during an experiment. These data were used to fit the model parameters of the FBG model. The dissertation includes a discussion of the effect of certain operating conditions such as bed temperature and liquid spray rate on a model parameter.

Steam explosions are possible during granulation of Si and FeSi75. These explosions are a great hazard, and must be avoided. Norwegian ferroalloy producers have initiated a research program to learn more about such violent melt-water interactions, in a joint effort with NTNU and SINTEF. The focus has primarily been on important parameters that can be controlled industrially, such as water temperature and metal composition. This thesis-work has focused on the effect of small additions of Al and Ca in Si-metal and FeSi75. However, within the same project, experiments on the effect of water temperature have also been carried out. The work has primarily been of experimental character. Two experimental apparatuses have been used. The first apparatus allows us to rapidly melt a sample of metal in an inert atmosphere to a desired temperature, expose the surface of the melt to an oxidizing agent (i.e. water) and then rapidly cool the sample to room temperature. The oxide that forms at the surface is examined with a microprobe. Thus, information regarding the composition and substance of the oxide layer is available. The second apparatus is suitable for releasing single drops of melt into a water tank, where they can be triggered and explode. A variety of techniques have been used in order to monitor the experiment: regular video, high-speed film, high-speed video, open-shutter imaging and pressure transducer measurements. Both Si and FeSi75 must be triggered in order to explode. Trigger pressures range from 0.3 MPa (FeSi75) to 2 MPa (Si-metal). We have established at which depths the molten drops can be triggered. Molten drops of FeSi75 can be triggered at depths twice of those of molten drops of Si. The latter can be triggered even if they are partially solidified. The explosion itself is strong enough to trigger neighbor drops as far away as 400 mm. Thus, we cannot rule out the possibility of large-scale steam explosions during granulation of molten Si or FeSi75, which is in accordance with industrial practice. By the use of high-speed imaging techniques and pressure measurements, we have been able to describe qualitatively what happens when a molten drop of Si/FeSi75 fragments rapidly in water. As the melt fragments, the rapid heat transfer generates vapor as bubbles, which expand and collapse in a cyclic manner. Large pressure pulses are generated upon collapse of the steam bubble, that is, when water jets impact in the center of the collapsing bubble. The first step in the oxidation of liquid silicon is the formation of gaseous SiO. The fate of this gas now depends on the flow conditions at the surface of the melt. In the case of a molten drop descending in water, most of the gas is flushed away from the surface. Thus, there are only minor traces of oxygencontaining material (i.e. silica) at the surface of the solidified drop. The addition of small amounts of Al and/or Ca dramatically changes the behavior of the molten drop. A strange effect is the two-fold increase in the fall velocity for molten drops of silicon. A similar effect was detected for molten drops of FeSi75. Alloying elements such as Al and Ca greatly reduce the risk for a steam explosion of molten Si. The significance of these elements is related to the oxidation reactions at the surface of the molten drop of metal. As silicon reacts with water vapor and oxidizes, hydrogen gas is formed. If Al and Ca are present in the melt, these elements will speed up the hydrogen generation considerably. This gas is strongly influencing on the probability for a steam explosion to occur. H2 stabilizes the vapor film around the drop, that is, much stronger trigger pressures are needed to collapse the film. Even if the trigger pressure is strong enough to collapse the vapor film, violent interactions are almost completely absent. A fragmentation of the melt is observed, but the heat transfer is apparently not rapid enough to generate steam bubbles, i.e. the generation of steam is below the critical limit.

Det här examensarbetet har utförts i samarbete med Metso:Outotec, där målet var att utföra en grundlig produktutvecklingsprocess för en lösning som möjliggör granulering direkt från en kaldo-konverter. Kaldo-processen är en batchprocess där man konverterar metall och tappar den i en skänk för vidare bearbetning. Med en lösning för att granulera metallen direkt från konvertern kan man undvika transport av flytande metall genom att samla processer på samma plats samt besparas behovet av en transferugn. Genom insamling av information via litteraturstudie och intervjuer identifierades behov som användes som grund för kravspecifikationen. Flertalet koncept togs fram och utvärderades med kravspecifikationen i beakting. Resultatet blev ett konceptförslag som innefattar ett parallellänkage med motvikt och nivåindikation som operatören använder för att styra flödet. Vid högre krav på flödeskontrollen finns möjlighet att montera en sensor och aktuator med pinnplugg för en automatisk flödeskontroll.

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.

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.

Malaria affects about forty percent of the world’s population. Annually more than 1.5 million fatalities due to malaria occur and parasite resistance to existing antimalarial drugs such as mefloquine has already reached disturbingly high levels in South-East Asia and on the African continent. Consequently, there is a dire need for new drugs or formulations in the prophylaxis and treatment of malaria. Artesunate, an artemisinin derivative, represents a new category of antimalarials that is effective against drug-resistant Plasmodium falciparum strains and is of significance in the current antimalarial campaign. As formulating an ACT double fixed-dose combination is technically difficult, it is essential that fixed-dose combinations are shown to have satisfactory ingredient compatibility, stability, and dissolution rates similar to the separate oral dosage forms. Since the general deployment of a combination of artesunate and mefloquine in 1994, the cure rate increased again to almost 100% from 1998 onwards, and there has been a sustained decline in the incidence of Plasmodium falciparum malaria in the experimental studies (Nosten et al., 2000:297; WHO, 2010:17). However, the successful formulation of a solid oral dosage form and fixed dosage combination of artesunate and mefloquine remains both a market opportunity and a challenge. Artesunate and mefloquine both exhibited poor flow properties. Furthermore, different elimination half-lives, treatment dosages as well as solubility properties of artesunate and mefloquine required different formulation approaches. To substantiate the FDA’s pharmaceutical quality by design concept, the double fixed-dose combination of artesunate and mefloquine required strict preliminary formulation considerations regarding compatibility between excipients and between the APIs. Materials and process methods were only considered if theoretically and experimentally proved safe. Infrared absorption spectroscopy (IR) and X-ray powder diffraction (XRPD) data proved compatibility between ingredients and stability during the complete manufacturing process by a peak by peak correlation. Scanning Electron Micrographs (SEM) provided explanations for the inferior flow properties exhibited by the investigated APIs. Particle size analysis and SEM micrographs confirmed that the larger, rounder and more consistently sized particles of the granulated APIs contributed to improved flow under the specified testing conditions. A compressible mixture containing 615 mg of the APIs in accordance with the WHO recommendation of 25 mg/kg of mefloquine taken in two or three divided dosages, and 4 mg/kg/day for 3 days of artesunate for uncomplicated falciparum malaria was developed. Mini-tablets of artesunate and mefloquine were compressed separately and successfully with the required therapeutic dosages and complied with pharmacopoeial standards. Preformulation studies eventually led to a formula for a double fixed-dose combination and with the specific aim of delaying the release of artesunate due to its short half-life. A factorial design revealed the predominant factors contributing to the successful wet granulation of artesunate and mefloquine. A fractional factorial design identified the optimum factors and factor levels. The application of the granulation fluid (20% w/w) proved to be sufficient by a spraying method for both artesunate and mefloquine. A compatible acrylic polymer and coating agent for artesunate, Eudragit® L100 was employed to delay the release of approximately half of the artesunate dose from the double fixed-dose combination tablet until a pH of 6.8. A compressible mixture was identified and formulated to contain 200 mg of artesunate and 415 mg of mefloquine per tablet. The physical properties of the tablets complied with BP standards. An HPLC method from available literature was adapted and validated for analytical procedures. Dissolution studies according to a USP method were conducted to verify and quantify the release of the APIs in the double fixed-dose combination. The initial dissolution rate (DRi) of artesunate and mefloquine in the acidic dissolution medium was rapid as required. The enteric coated fraction of the artesunate exhibited no release in an acidic environment after 2 hours, but rapid release in a medium with a pH of 6.8. The structure of the granulated particles of mefloquine may have contributed to its first order release profile in the dissolution mediums. A linear correlation was present between the rate of mefloquine release and the percentage of mefloquine dissolved (R2 = 0.9484). Additionally, a linear relationship was found between the logarithm of the percentage mefloquine remaining against time (R2 = 0.9908). First order drug release is the dominant release profile found in the pharmaceutical industry today and is coherent with the kinetics of release obtained for mefloquine. A concept pre-clinical phase, double fixed-dose combination solid oral dosage form for artesunate and mefloquine was developed. The double fixed-dose combination was designed in accordance with the WHO’s recommendation for an oral dosage regimen of artesunate and mefloquine for the treatment of uncomplicated falciparum malaria. The specifications of the double fixed-dose combination were developed in close accordance with the FDA’s quality by design concept and WHO recommendations. An HPLC analytical procedure was developed to verify the presence of artesunate and mefloquine. The dissolution profiles of artesunate and mefloquine were investigated during the dissolution studies. / PhD (Pharmaceutics), North-West University, Potchefstroom Campus, 2014

Malaria affects about forty percent of the world’s population. Annually more than 1.5 million fatalities due to malaria occur and parasite resistance to existing antimalarial drugs such as mefloquine has already reached disturbingly high levels in South-East Asia and on the African continent. Consequently, there is a dire need for new drugs or formulations in the prophylaxis and treatment of malaria. Artesunate, an artemisinin derivative, represents a new category of antimalarials that is effective against drug-resistant Plasmodium falciparum strains and is of significance in the current antimalarial campaign. As formulating an ACT double fixed-dose combination is technically difficult, it is essential that fixed-dose combinations are shown to have satisfactory ingredient compatibility, stability, and dissolution rates similar to the separate oral dosage forms. Since the general deployment of a combination of artesunate and mefloquine in 1994, the cure rate increased again to almost 100% from 1998 onwards, and there has been a sustained decline in the incidence of Plasmodium falciparum malaria in the experimental studies (Nosten et al., 2000:297; WHO, 2010:17). However, the successful formulation of a solid oral dosage form and fixed dosage combination of artesunate and mefloquine remains both a market opportunity and a challenge. Artesunate and mefloquine both exhibited poor flow properties. Furthermore, different elimination half-lives, treatment dosages as well as solubility properties of artesunate and mefloquine required different formulation approaches. To substantiate the FDA’s pharmaceutical quality by design concept, the double fixed-dose combination of artesunate and mefloquine required strict preliminary formulation considerations regarding compatibility between excipients and between the APIs. Materials and process methods were only considered if theoretically and experimentally proved safe. Infrared absorption spectroscopy (IR) and X-ray powder diffraction (XRPD) data proved compatibility between ingredients and stability during the complete manufacturing process by a peak by peak correlation. Scanning Electron Micrographs (SEM) provided explanations for the inferior flow properties exhibited by the investigated APIs. Particle size analysis and SEM micrographs confirmed that the larger, rounder and more consistently sized particles of the granulated APIs contributed to improved flow under the specified testing conditions. A compressible mixture containing 615 mg of the APIs in accordance with the WHO recommendation of 25 mg/kg of mefloquine taken in two or three divided dosages, and 4 mg/kg/day for 3 days of artesunate for uncomplicated falciparum malaria was developed. Mini-tablets of artesunate and mefloquine were compressed separately and successfully with the required therapeutic dosages and complied with pharmacopoeial standards. Preformulation studies eventually led to a formula for a double fixed-dose combination and with the specific aim of delaying the release of artesunate due to its short half-life. A factorial design revealed the predominant factors contributing to the successful wet granulation of artesunate and mefloquine. A fractional factorial design identified the optimum factors and factor levels. The application of the granulation fluid (20% w/w) proved to be sufficient by a spraying method for both artesunate and mefloquine. A compatible acrylic polymer and coating agent for artesunate, Eudragit® L100 was employed to delay the release of approximately half of the artesunate dose from the double fixed-dose combination tablet until a pH of 6.8. A compressible mixture was identified and formulated to contain 200 mg of artesunate and 415 mg of mefloquine per tablet. The physical properties of the tablets complied with BP standards. An HPLC method from available literature was adapted and validated for analytical procedures. Dissolution studies according to a USP method were conducted to verify and quantify the release of the APIs in the double fixed-dose combination. The initial dissolution rate (DRi) of artesunate and mefloquine in the acidic dissolution medium was rapid as required. The enteric coated fraction of the artesunate exhibited no release in an acidic environment after 2 hours, but rapid release in a medium with a pH of 6.8. The structure of the granulated particles of mefloquine may have contributed to its first order release profile in the dissolution mediums. A linear correlation was present between the rate of mefloquine release and the percentage of mefloquine dissolved (R2 = 0.9484). Additionally, a linear relationship was found between the logarithm of the percentage mefloquine remaining against time (R2 = 0.9908). First order drug release is the dominant release profile found in the pharmaceutical industry today and is coherent with the kinetics of release obtained for mefloquine. A concept pre-clinical phase, double fixed-dose combination solid oral dosage form for artesunate and mefloquine was developed. The double fixed-dose combination was designed in accordance with the WHO’s recommendation for an oral dosage regimen of artesunate and mefloquine for the treatment of uncomplicated falciparum malaria. The specifications of the double fixed-dose combination were developed in close accordance with the FDA’s quality by design concept and WHO recommendations. An HPLC analytical procedure was developed to verify the presence of artesunate and mefloquine. The dissolution profiles of artesunate and mefloquine were investigated during the dissolution studies. / PhD (Pharmaceutics), North-West University, Potchefstroom Campus, 2014

Malaria is a life–threatening disease caused by Plasmodium spp and causes over one million deaths annually. The complex life cycle of the malaria parasite offers several points of attack for the antimalarial drugs. The rapid spread of resistance against antimalarial drugs, especially chloroquine and pyrimethamine–sulphadoxine, emphasises the need for new alternatives or modification of existing drugs. Artemisinin–based combination therapies (ACT’s) with different targets prevent or delay the development of drug resistance and therefore have been adopted as first–line therapy by all endemic countries. Proguanil–dapsone, an antifolate combination is more active than pyrimethamine–sulphadoxine and is being considered as an alternative to pyrimethamine–sulphadoxine. Artesunate–proguanil–dapsone is a new ACT that has wellmatched pharmacokinetics and is relatively rapidly eliminated; therefore there is a reduced risk of exposure to any single compound and potentially a decreasing risk of resistance. A few studies have been done on a triple fixed–dose combination therapy for malaria treatment and such a combination for artesunate, proguanil and dapsone are not currently investigated, manufactured or distributed. The aim of this study was to develop a triple fixed–dose combination for artesunate, proguanil and dapsone. The formulation was developed in three phases; basic formulation development, employing factorial design to obtain two possible optimised formulations and evaluating the optimised formulations. During the formulation development the most suitable manufacturing procedure and excipients were selected. A full 24 factorial design (four factors at two levels) was used to obtain the optimised formulations. As end–points to identify the optimised formulations, weight variation, friability, crushing strength and disintegration of the tablets, were used. Statistical analysis (one way ANOVA) was used to identify optimal formulations. To identify any interaction between the active pharmaceutical ingredients (API’s) and the API’s and excipients, differential scanning calorimetry was done. Flow properties of the powder mixtures (of the optimised formulations) were characterised by means of angle of repose; critical orifice diameter (COD); bulk density and tapped density; and flow rate. Tablets of the two optimised powder formulations were compressed. The tablets were evaluated and characterised in terms of weight variation, friability, crushing strength, disintegration and dissolution behaviour. Initial formulation development indicated that wet granulation was the most suitable manufacturing method. The results from the factorial design indicated that different amounts (% w/w) of the lubricant and binder as well as two different fillers influenced the weight variation, crushing strength and disintegration statistically significant. Two formulations containing two different fillers (microcrystalline cellulose or Avicel® PH 101, and lactose or Granulac® 200) were found to be within specifications and ideal for manufacturing. Tablets prepared from the FA formulation (formulation containing Avicel® PH 101) complied with the standards and guidelines for weight variation, friability, crushing strength and disintegration as set by the British Pharmacopoeia (BP). Tablets had an average crushing strength of 121.56 ± 0.022 N. Tablets disintegrated within 52.00 seconds and a maximum weight loss of 0.68% occurred during the friability test. Weight variation of the tablets prepared from the FG formulation (formulation containing Granulac® 200) complied with the standards. Average crushing strength was 91.99 ± 6.008 N and the tablets disintegrated within 140.00 seconds. Percentage friability (1.024%) did not comply with the guideline of a percentage friability of less than 1%, however, no cracked or broken tablets were seen. Dissolution showed that 98, 93 and 94% of artesunate, proguanil and dapsone were respectively released (of the label value) within 15 minutes for the FA formulations. Release of artesunate, proguanil and dapsone for the FG formulation was 62, 85 and 92% for the same time period. The release of the three API’s (the FG formulation) increased to 78, 89 and 92%, respectively, after 45 minutes. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2012.