In this research we tried to optimize the process of spherical crystallization of lactose, more precisely diffusion of solvent from quasi-emulsion. Definitive screening design (thereinafter DSD) was used for optimization which gives optimum product demanding smaller number of experiments. Our goal was to obtain good yield of particles with good flow properties which can be used further. Temperature of crystallization system, volume ratio of non-solvent versus crystallization system, mixing speed, lactose concentration in solution, solution adding speed and type of non-solvent were studied to recognize the effect on particle properties. Yield, particle size (D10, D50, D90), particle size distribution and Hausner ratio were evaluated. We were able to identify active effects and construct a model for each property from obtained results using DSD. Most relevant active effect was lactose concentration, which affected most properties, except D10 (particle size). Volume ratio of non-solvent versus crystallization system was also relevant and had a negative effect on D10 and D50 and had no effect on D90. Type of non-solvent affected yield, D90, particle size distribution and Hausner ratio. Most complex effects were obtained at D50 because of first order effects and negative square effect of lactose concentration, one positive two factor interaction (lactose concentration x solution adding speed) and one negative two factor interaction (lactose concentration x volume ratio). Besides, negative effect of solution adding speed at D50 was present, which also affected yield and D90. Temperature of crystallization system and mixing speed did not affect particle properties under given experimental conditions. Using optimization experiment at the end, we prepared particles that were excellent for direct tableting because of compressibility comparable to commercial types of lactose and even better compactibility that commercial particles possess. Tablets also have a very good porosity at high tablet hardness, which allows usage of particles in immediate release formulations.