RESUMO
Chlorproguanil hydrochloride, dapsone and artesunate are three compounds with anti-malarial properties developed as a triple combination drug product (Dacart™) for the treatment of malarial infections. During long-term stability studies, a degradant was observed which increased with time and had the potential to limit the shelf-life of the product. Through a combination of HPLC and spectroscopic analyses, the structure of the degradant was identified to be an adduct of a fragment of artesunate with dapsone. The response factor was determined to allow an accurate assessment of its levels in drug product. The likely mechanism for its formation is postulated to be via the water-mediated degradation of artesunate to give succinic acid followed by reaction of the liberated succinic acid with dapsone. The formation of this degradant demonstrates a potential stability risk for future combination therapies incorporating artesunate. These risks are particularly pertinent to products of this type given the climatic conditions which prevail in countries where such therapies are likely to be employed.
Assuntos
Antimaláricos/química , Artemisininas/química , Dapsona/química , Proguanil/análogos & derivados , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Artesunato , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Dapsona/uso terapêutico , Combinação de Medicamentos , Estabilidade de Medicamentos , Quimioterapia Combinada , Temperatura Alta , Humanos , Umidade , Espectroscopia de Ressonância Magnética , Malária Falciparum/tratamento farmacológico , Espectrometria de Massas , Proguanil/química , Proguanil/uso terapêutico , ComprimidosRESUMO
The purpose of this study was to develop a method of qualitatively predicting the most likely degradants in a formulation or probing specific drug-excipient interactions in a significantly shorter time frame than the typical 1 month storage testing. In the example studied, accelerated storage testing of a solid dosage form at 50 degrees C, the drug substance SB-243213-A degraded via the formation of two oxidative impurities. These impurities reached a level of 1% PAR after 3 months. Various stressing methods were examined to try to recreate this degradation and in doing so provide a practical and reliable method capable of predicting drug-excipient interactions. The technique developed was able to mimic the 1-month's accelerated degradation in just 1 hr. The method was suitable for automated analysis, capable of multisample stressing, and ideal for use in drug-excipient compatibility screening.
