At present, the way of purifying sulbactam sodium is to synthesize sulbactam sodium by sulbactam acid, which is obtained by reduction reaction. The method is time-consuming, labor-intensive and requires a large variety of drugs and reagents, and is not energy-saving and environmentally friendly. For this problem, the orthogonal experiment was used to optimize the anti-solvent crystallization of sulbactam sodium. The effects of six factors and three interactions on crystal size distribution, purity and comprehensive scores of the two were considered, included aging time (A), volume of anti-solvent used(B), volume fraction of ethanol in the anti-solvent(C), rate of addition of the anti-solvent (D), stirring rate (E), crystallization temperature(F), and the interaction between the aging time and the volume of the anti-solvent (A×B), the interaction between the aging time and the volume fraction of ethanol in the decanting agent (A×C), the interaction between the volume of the anti-solvent used and the volume fraction of ethanol in the anti-solvent(B×C) . The results of variance analysis showed: the used volume of anti-solvent (B) has the most significant effect on crystal size distribution(CSD), but other factors and interactions are not significant; the volume fraction of ethanol in the anti-solvent(C), the dropping rate of the anti-solvent(D), the stirring rate (E) and the interaction between the aging time and the volume fraction of ethanol in the anti-solvent(A×C) have a highly significant impact on the purity, and both of interaction between the crystallization time and the volume of the anti-solvent(A×B), and the interaction between the volume of anti-solvent used and the volume fraction of ethanol in the anti-solvent(B×C) have a significant effect, but the others are not significant; when the significant level α is between 0.10 and 0.025, considering the purity-CSD at a ratio of 70% and 30% respectively, volume of the anti-solvent used(B) and the volume fraction of ethanol in the anti-solvent(C) are highly significant, and others are not significant. The optimal operating level combination is A 2 B 2 C 1 D 3 E 3 F 2. Repeated validation tests yielded: the purity of sulbactam sodium raw material can be increased from 79.58% to over 97% by only once anti-solvent crystallization, and the crystal size distribution D[4,3] can be increased from 41.1μm to above 290μm. The mass fraction yield of sulbactam sodium obtained by multiple confirmatory experiments is about 84%. It is found that the impurity sulbactam penicillamine has a certain influence on the particle size distribution of sulbactam sodium. On the basis of solving the original problems, the sulbactam sodium product with suitable particle size distribution can also provide convenience for the subsequent preparation process.