**1. Introduction**

Melatonin (MLT) is an indole amide hormone produced by the pineal gland, especially at night time and is mainly involved in the regulation of circadian and circannual rhythms. For clinical purposes (including Alzheimer's disease, insomnia, stroke, depression, Parkinson's disease, migraine, headache, etc.), exogenous MLT could be administered for alleviation of the symptoms. Irrespective of the pathological case, MLT's exogenous administration should mimic the typical nocturnal endogenous MLT levels. The release profile of these drug delivery systems should be in a controlled manner, due to MLT's short half-life of elimination and low bioavailability.

The development of novel pharmaceutical formulations with the optimal release profile is of great importance for cases like melatonin. To this purpose, a series of experiments should be performed, utilizing various excipients at different ratios. These trials could require plenty of working hours, with no guarantee that, indeed, the optimal formulation composition will be reached. Therefore, the employment of a statistical/chemometric approach, such as design of experiments (DoE), can be beneficial for complicated and demanding tasks like the development of modifiedrelease formulations with a minimum number of experiments.
