Artemisinin-based combination therapies, including artesunate (AS) + amodiaquine (AQ), are the currently recommended first-line treatment of uncomplicated falciparum malaria. Fixed-dose co-formulations offer logistic and adherence advantages. This paper reports the initial research phase of the pre-development process of an AS-AQ formulation, further developed by the Drug for Neglected Diseases Initiative (DNDi). Results demonstrate that AS and AQ are not compatible, and AS degradation is related to three main parameters: water content (>1%), elevated temperature (80 degrees C in dry condition) and possibly the 4-aminoquinoline moiety. Furthermore, AS and AQ incompatibility led to AS degradation and pharmaco-technical changes in classical wet granulation tablets. Both active principles are stable as dry powders. These investigations led to further development of various co-formulations, including the bilayer tablet currently on the market.