Excipient’s homogeneity is of paramount importance during the development of pharmaceutical formulations due to its relation to stability, safety and efficacy. A direct and unique approach to evaluate such property is 3D Raman imaging. This technique characterizes the surface and inner part of preformulation samples, allowing to determine phase separation in the early stages of pharmaceutical development. Aiming to promote controlled release of the local anesthetic butamben (BTB), confocal 3D Raman microscopy was used to obtain its optimal proportion in Apifil®, Capryol® 90 and Transcutol®. Even if the microscopic images of some samples displayed very homogeneous surfaces, analysis of 3D maps showed that chemical distribution throughout the material was different. To investigate how concentration affects the homogeneity, mixture experimental design (DoE) was employed. From this analysis, it was revealed that correct amount of Capryol® 90 enhances both miscibility and solubility. Furthermore, suitable miscibility was observed in two ratio proportions of excipients: Solution 1: Apifil® 30.00%, Capryol 20.00% and Transcutol 10.00% (w/w), with a desirability of 0.783; and Solution 2: Apifil® 25.00%, Capryol 25.00% and Transcutol 10.00% (w/w), with 0.742 desirability. These results unequivocally demonstrated that confocal Raman microscopy combined to DoE can bring pharmaceutical development to a higher level.