Abstract: Spiramycin and its acylated derivative, multicomponent macrolide antibiotic, have high lipotropy and excellent antibacterial effect in clinical medicine. However, most of acylated spiramycin products are powder crystal prepared by reaction crystallization which absorb moisture and agglomerate easily, compromising their storage and subsequent processing in industry. This paper focuses on using the spherical crystal preparation technology, the quasi emulsion solvent diffusion method, to improve the crystal morphology and enrich the active ingredients of acylated spiramycin. An oil in water emulsion system of solvent and water under high shear and emulsification of polymer excipient (HPMC E50) was generated in a jacket crystallizer. During this process, acylated spiramycin precipitated and agglomerated into spherical crystal with solvents diffusing in emulsion droplets. Finally, based on the study of the key effects of the spherical crystallization process, the optimal parameters were obtained: system temperature is 30 ℃, volume ratio of solvent to water is 0.030, resident time is 5 h, stirring rate is 500 r/min. Both the average diameter and unity of spherical crystal product are increased significantly (D₄₃ is 365 μm, consistency index is 0.213) compared with raw material (D₄₃ is 10.97 μm, consistency index is 0.897). Moreover, the content of main effective component was increased by 5% with the mass yield no less than 75%. The product yield can be improved when using K₂HPO₄ solution with a mass concentration greater than 2%, but the standing time needs to be strictly controlled to avoid reduction of production purity caused by the hydrolysis of acylated spiramycin.