*2.3. Effect of γ-CD on Efavirenz Solubility*

The solubilising effect of medicinal applications of γ-CD on efavirenz was evaluated by collecting the solubility isotherm for this API while in the presence of increasing concentrations of the host. Results are shown in Figure 7. The aqueous solubility reported for efavirenz is very low, with values between 0.0127 mM [32] and 0.0263 mM [33]. The isotherm data herein shown demonstrates that the presence of 37.7 mM γ-CD in solution increases the solubility of efavirenz to 0.124 mM, that is, by at least 5-fold. Efavirenz solubility increases further with the increase in concentration of γ-CD in aqueous solution, with 0.565 mM of EFV dissolved when γ-CD concentration is 75.0 and 1.424 mM of EFV dissolved for the γ-CD concentration of 112.5 mM. After this point, a plateau is reached, indicating the formation of aggregates containing only γ-CD molecules. Self-aggregation of γ-CD molecules is well known, and it can be attributed to their symmetry and extensive intermolecular hydrogen bonding.

**Figure 7.** Phase solubility isotherm for efavirenz (EFV) in the presence of γ-CD.

For a brief discussion of these results, it is worth comparing them with those of β-CD, HPβCD, RAMEB and HPγCD, previously reported as solubilisers for EFV. The effect of RAMEB on EFV solubility was equivalent to that of γ-CD, with 80 mM of RAMEB solubilising roughly 0.5 mM of this guest [19]. Nevertheless, RAMEB is only approved for topical use (at the nasal and ocular mucosa), which limits its interest as a solubilising agent [14]. Regarding HPβCD, the literature shows contradictory data, one study depicting it as a good solubiliser, with 60 mM increasing EFV solubility to roughly 1 mM [19], whereas our previous report, in which the isotherm data were collected under the same conditions as those of the present study, revealed it to perform worse than γ-CD, since a concentration of 125 mM of HPβCD was required to solubilise ca. 0.5 mM of EFV [20]. Our study also evaluated HPγCD, which had an isotherm similar to that of HPβCD up to 150 mM and performed slightly worse at higher concentrations [20].
