Procedures for optimization of factor by multivariate techniques have been encouraged, as they are faster, more economical and effective, and allow more than one variable to be optimized simultaneously. Chemmometric techniques have been used for optimization of analytical methods. These techniques allow the simultaneous study of several control variables, which are faster to implement and more cost-effective than traditional univariate approaches. Among these techniques, the most popular is the two-level full factorial, in which every factor is experimentally studied at only two levels. These design structures are based on full two-level factorial design by center point replication and inclusion of an axial portion. Several digestion procedures for natural sample have been optimized using this chemometric tool.