2.2.4. Thermogravimetric Analysis

The thermograms of efavirenz, γ-CD heptahydrate and the two freeze-dried products, (γ-CD)3·(EFV)<sup>2</sup> and γ-CD·EFV, are represented in Figure 6. The thermogram of pure efavirenz shows no mass losses from ambient temperature until about 185 ◦C, temperature that marks the onset of its decomposition. The absence of mass losses at temperatures lower than 100–130 ◦C indicates the absence of hydration waters, which is expectable due to the apolar nature of this compound. In turn, the thermogram of γ-CD heptahydrate is marked by an initial dehydration step that starts at ambient temperature and proceeds up to 95 ◦C. This step features a mass loss of 9% that translates into seven hydration waters, being thus coherent with the original specifications.

**Figure 6.** Thermogravimetry traces for efavirenz, γ-CD, and the freeze-dried adducts (γ-CD)<sup>3</sup> ·(EFV)<sup>2</sup> and γ-CD·EFV.

The thermogravimetric traces of the two freeze-dried products are marked by an increase in the number of hydration waters. This is evidenced by a more intense dehydration step, rounding 15.5%. For the 3:2 complex, the results allow inferring a general formula of (γ-CD)3·(EFV)2·(H2O)39. The increase in the number of hydration waters in comparison to those exhibited by the host is a characteristic of γ-CD inclusion complexes and it results from their distinctive tetragonal symmetry. As described in the section referring to PXRD, γ-CD molecules pack, with the guest molecules lodged inside the channel cavity and also with the formation of wide inter-channel spaces that are able to retain a large number of water molecules (see inset in Figure 4). Literature examples of γ-CD complexes with a large number of hydration waters include γ-CD·quercetin·(H2O)<sup>17</sup> [29], γ-CD·fisetin·(H2O)<sup>17</sup> [30], and (γ-CD)3·(resveratrol)4·(H2O)<sup>62</sup> [31], to name only a few.

The presence of a strong dehydration step in the trace corresponding to the 1:1 sample is also indicative of the presence of an inclusion complex, however, the mass loss observed between ca. 180 and 220 ◦C denotes contamination with some amount of pure efavirenz that decomposes at this temperature. It is important to highlight that the step associated with efavirenz thermal decomposition is absent from the thermogram of (γ-CD)3·(EFV)2, which provides definitive corroboration of the presence of the pure inclusion complex in this sample.
