The aim of present study was to use QbD approaches to evaluate the effect of independent product variables and their interaction on particle size of sodium fluoride and then obtain the optimized experimental condition for predefined particle size of sodium fluoride. The sodium fluoride is mainly used in dental preparation for delivering the fluoride ion to the tooth enamel for that nano-particle size is required. Now a days the milling process is use to reduce the particle size. But that process having some limitations because of crystalline nature of sodium fluoride, for overcomes that problem lyophilization method is used. A 43 level full factorial design was used to study the significant influence of process and product variables i.e.1) Concentration of sodium fluoride,2)concentration of PVP, 3)Sample volume,4)Drying surface, on particle size of sodium fluoride.