A comparative study related to the preparation of poly(2-hydroxyethyl methacrylate) (pHEMA) through radical polymerization process in the presence of three different protective colloid substances, respectively poly(vinyl alcohol) (PVA), β-cyclodextrin, or poly(aspartic acid) (PAS), is presented. The dependence of the thermal behavior of the polymers as well as their morphological aspect, on the protective colloids used in synthesis was evidenced by polymers characterization. It is also demonstrated that the swelling capacity is dependent on the protective colloid variant present during the pHEMA preparation. This behavior induces as well interdependence on the ability to load bioactive compounds onto the polymeric matrices. The distribution of the indomethacin (INN), as model drug, into the pHEMA network was put into evidence by near infrared chemical imaging (NIR-CI), a non-destructive technique and with its correspondingly statistical analysis.