To improve the dissolution properties and the physical stability of amorphous active pharmaceutical ingredients, small molecule stabilizing agents may be added to prepare co-amorphous systems. The objective of the study was to investigate if spray-drying allows the preparation of co-amorphous drug–drug systems such as naproxen–indomethacin and to examine the influence of the process conditions on the resulting initial sample crystallinity and the recrystallization behavior of the drug(s). For this purpose, the process parameters inlet temperature and pump feed rate were varied according to a 22 factorial design and the obtained samples were analyzed with X-ray powder diffractometry and Fourier-transformed infrared spectroscopy. Evaluation of the data revealed that the preparation of fully amorphous samples could be achieved depending on the process conditions. The resulting recrystallization behavior of the samples, such as the total recrystallization rate, the individual recrystallization rates of naproxen and indomethacin as well as the polymorphic form of indomethacin that was formed were influenced by these process conditions. For initially amorphous samples, it was found that naproxen and indomethacin recrystallized almost simultaneously, which supports the theory of formation of drug–drug heterodimers in the co-amorphous phase. ; To improve the dissolution properties and the physical stability of amorphous active pharmaceutical ingredients, small molecule stabilizing agents may be added to prepare co-amorphous systems. The objective of the study was to investigate if spray-drying allows the preparation of co-amorphous drug-drug systems such as naproxen-indomethacin and to examine the influence of the process conditions on the resulting initial sample crystallinity and the recrystallization behavior of the drug(s). For this purpose, the process parameters inlet temperature and pump feed rate were varied according to a 2(2) factorial design and the obtained samples were analyzed with X-ray powder diffractometry and Fourier-transformed infrared spectroscopy. Evaluation of the data revealed that the preparation of fully amorphous samples could be achieved depending on the process conditions. The resulting recrystallization behavior of the samples, such as the total recrystallization rate, the individual recrystallization rates of naproxen and indomethacin as well as the polymorphic form of indomethacin that was formed were influenced by these process conditions. For initially amorphous samples, it was found that naproxen and indomethacin recrystallized almost simultaneously, which supports the theory of formation of drug-drug heterodimers in the co-amorphous phase.