Spherical agglomerates of pharmaceuticals are desired in the manufacturing process, however, the current selection of the wetting liquid is still determined in a trial-and-error way. This work reports a method that combines theoretical prediction and experimental validation to select the proper wetting liquid for spherical agglomeration of cefotaxime sodium (CTX). The theoretical prediction is realized by calculating the adhesion free energy between the solid surfaces and the liquid. Various solvents have been screened and candidates with a negative adhesion free energy such as water, chloroform, ethylene glycol, hexane and heptane are selected as wetting liquid candidates. Results show that the adhesion free energy is a feasible tool for selecting a suitable wetting liquid to produce spherical agglomerates. Better-shaped and uniformed spherical agglomerates are obtained with the suitable wetting liquid via orthogonal experiments. Finally, the spherical agglomeration process is visualized and possible mechanism is proposed. Display omitted •The proper wetting liquid for spherical agglomeration of cefotaxime sodium (CTX) is decided by theoretical prediction.•Spherical agglomerates of CTX are produced by spherical agglomeration using the predicted wetting liquids.•A possible mechanism for the SA process of CTX is proposed.