Formation and identification of a degradant in chlorproguanil-dapsone-artesunate (Dacart™) tablets

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.