Responsive hydrogels are one of the most frequently proposed vehicles for targeted and controlled drug delivery. Interaction between the transported drug and the three-dimensional polymer network could compromise the kinetics and the efficiency of delivery in thermoresponsive polymers. Poly(N-isopropylacrylamide) (PNIPA) gel was equilibrated with excess 500 mM aqueous solutions of three model drug molecules, phenol, ibuprofen and dopamine. These molecules affect the swelling properties of PNIPA in different ways. After determining the drug uptake and drying to constant mass the loaded samples were studied with simultaneous thermal analysis (STA). The difference in thermal response is interpreted in terms of the different typical molecular interactions in these systems under confined conditions. For phenol and dopamine the water -phenol and dopamine -dopamine interactions, respectively, are stronger than that between the guest and polymer. For ibuprofen -PNIPA the synergy in the thermal decomposition may stem from a strong polymeribuprofen relation.