2.1.3. Thermal Analysis

In order to evaluate the interaction between RSP and RM-β-CD in solid state, the thermal behavior of parent substances, their physical mixture (PM), and kneaded product (KP) have been investigated using TG, DTG, and HF. The thermoanalytical curves of RSP, CD, RSP/RM-β-CD binary systems obtained by physical mixture (PM) and by kneading (KP) are shown in Figure 4a–d.

**Figure 4.** The thermal profile (TG-thermogravimetry/DTG-derivative thermogravimetry/HF-heat flow) of: RSP (**a**); RM-β-CD (**b**); RSP/RM-β-CD physical mixture (**c**); and kneaded product (**d**) in air atmosphere (100 mL/min), temperature range of 40–500 ◦C and heating rate of 10 ◦C/min.

Detailed interpretation of the RSP thermal profile is presented in our previous paper [22]. The drug substance exhibits thermal stability up to 206 ◦C, which is a temperature that marks the onset of its decomposition; then, a continuous mass loss process is observed up to 510 ◦C (∆*m* = 55.6%). As the DTG curve shows, RSP thermal decomposition takes place in three stages: the first one is noticed between 200 and 226 ◦C (peak at 209 ◦C); the second is in the temperature range of 226–350 ◦C (main peak at 319 ◦C); and the last one is between 350 and 474 ◦C (peak at 391 ◦C) [22]. RSP melting is revealed as an endothermic peak at 173 ◦C in the HF curve (Figure 4a) [30,44]. In addition, a small exothermic peak is noticed at 259 ◦C that corresponds to the first process of RSP thermal degradation; above 474 ◦C, the degradation occurs rapidly confirmed by the exothermic effect on HF and the rapid mass loss on the TG curve [22].

The thermoanalytical curves of RM-β-CD reveal a small mass loss (∆*m* = 5.3%) between 40 and 85 ◦C and an endothermic effect (peak at 52.0 ◦C) which relates to the

crystallization water loss (Figure 4b). A stability stage of CD is observed in the temperature range of 85–270 ◦C, but above 270 ◦C, the mass loss continues, and the degradation process takes place as the exothermic event (peak at 361.0 ◦C) of the HF curve indicates [19].

The thermal curves of RSP/RM-β-CD binary systems present significant differences as compared to those of the pure substances. Both the endothermic melting peak of RSP and the RSP exothermic effect are no more present neither in the HF curve of PM nor in that of KP. In addition, the endothermic events at 361.0 ◦C and 500 ◦C from the HF curve of RM-β-CD are displaced at lower temperature in HF curves of PM (357 ◦C and 477 ◦C, Figure 4c) and KP (the first event disappeared, second at 487 ◦C, Figure 4d). On the other hand, the TG curves of binary systems reveal a decrease in thermal stability of RSP (∆*m* = 55.6%) in temperature range of 38–510 ◦C in both PM (∆*m* = 89.7%) and KP (∆*m* = 89.2%); this phenomenon may be a consequence of the crystallinity reduction of drug substance as a result of interaction with RM-β-CD [45]. Furthermore, the decomposition pathway of RSP in the PM and KP differs from that of pure drug substances as the DTG curves show; two distinct regions can be noticed in the DTG of KP, while the DTG of PM shows only one stage.

Thermal methods are valuable tools frequently used to investigate the interaction between CD and drug substances and to prove the encapsulation of guest molecule in the host cavity [46–48]. The guest–host interaction is characterized by changes in the thermal profiles of guest substances in the inclusion complex. The melting point of the guest molecule, which is embedded in the CD cavity, generally shifts to a different temperature and decreases its intensity or disappears [14,21,49]. The above-mentioned changes in the RSP thermal profile in the RSP/RM-β-CD binary products provide evidence for an interaction between the drug substance and CD as a result of inclusion complex formation.
