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