The present study was undertaken to investigate the effect of the composition of the polymerization medium and the type of drug/drug loading process on the mechanical strengths and release profiles of poly(N-isopropylacrylamide-co-N-[3-(dimethylamino)propyl] methacrylamide) P(NIPAAm-co-DMAPMAAm) hydrogels. In line with this goal firstly, the temperature- and pH-responsive hydrogels of NIPAAm and DMAPMAAm were synthesized in three different media at 60 degrees C: pH 7.4 phosphate-buffered saline (PBS), pH 7.4 phosphate buffer without NaCl/KCl (PB), and distilled-deionized water (pH approximate to 5.5 DDW). The result is that the presence of anionic species such as phosphate (HPO42-/H2PO4-) and chloride (Cl-) ions in the solution affects on their basic network properties such as volumetric swelling ratio and compression modulus. To evaluate their intermolecular interactions with protonated DMAPMAAm units and drug molecules, depending on composition, type of loading process and drug structure, each of the hydrogels was loaded with diclofenac sodium (DFNa) and theophylline (Thp) by using both diffusion and in situ loading methods. DFNa and Thp release profiles in pH 7.4 PBS at 37 degrees C were analysed by using zero-order, first-order, Higuchi, Korsmeyer-Peppas, and Peppas-Sahlin models. It has been observed that for the first 60% of DFNa and Thp releases from P(NIPAAm-co-DMAPMAAm) hydrogels synthesized in PB at 60 degrees C, the contribution of the chain relaxation for the copolymer hydrogels loaded during gelation process was higher than the ones loaded by diffusion process.