Micronization is frequently employed to increase the dissolution of poorly soluble drugs, but it easily led to powder aggregation and difficult to mix well on the micro level with poor content uniformity and erratic dissolution behavior. Mannitol is the most commonly used pharmaceutical excipient, and its β form (β-mannitol) is commercially available and extensively investigated, whereas form α (α-mannitol) remain poorly understood. Here, this study demonstrated that α-mannitol could significantly eliminate aggregation phenomena of micronized drugs (i.e., lurasidone hydrochloride, indomethacin and ibuprofen) after general mixing, while β-mannitol could not. In addition, the drug dissolutions after mixing with α-mannitol were also significantly higher than that with β one. This stemmed from the different molecular orientation on their dominant crystal facets, resulting in greater number of unsaturated hydrogen bonds site (0.050 Å