Abstract. Although using spray-dried dispersions (SDDs) to improve the bioavailability of poorly watersoluble compounds has become a common practice in supporting the early phases of clinical studies, their performance evaluation, whether in solid dosage forms or alone, still presents significant challenges. A microcentrifuge dissolution method has been reported to quickly assess the dissolution performance of SDDs. While the microcentrifuge dissolution method has been used in the SDD community, there is still a need to understand the mechanisms about the molecular species present in supernatant after centrifugation, the molecular nature of active pharmaceutical ingredients (APIs), as well as the impact of experimental conditions. In this paper, we aim to assess the effect of API and polymer properties on the dissolution behavior of SDDs along with centrifuging parameters, and for this, two poorly water-soluble compounds (indomethacin and ketoconazole) and two commonly used polymers in the pharmaceutical industry (PVP and HPMC-AS) were chosen to prepare SDDs. A typical microcentrifuge dissolution procedure as reported in the publication (Curatolo et al., Pharm Res 26:1419-1431, 2009) was followed. In addition, after separation of the supernatant from precipitation, some of the samples were filtered through filters of various sizes to investigate the particulate nature (particle size) of the supernatant. Furthermore, the centrifuge speed was varied to study sedimentation of API, SDD, or polymer particles. The results indicated that for the SDDs of four drug-polymer pairs, microcentrifuge dissolution exhibited varied behaviors, depending on the polymer and the drug used. The SDDs of indomethacin with either PVP or HPMC-AS showed a reproducible dissolution with minimum variability even after filtration and subjecting to varied centrifugation speed, suggesting that the supernatant behaved solution-like. However, ketoconazole-PVP and ketoconazole-HPMC-AS SDDs displayed a significant variation in concentration as the speed of centrifugation and the pore sizes of filters were altered, indicating that their supernatant was heterogeneous with the presence of particulates. In conclusion, microcentrifuge dissolution method was more suitable for indomethacin-PVP and indomethacin-HPMC-AS systems compared with ketoconazole-PVP and ketoconazole-HPMC-AS. Therefore, the use of microcentrifuge dissolution method depends on both compounds and polymers selected, which should be examined case by case.