**1. Introduction**

Efavirenz (EFV) is a potent antiretroviral of widespread use as first-line therapy for patients with HIV infection. Administered in the form of a tablet and requiring only one dose per day [1], efavirenz is a practical therapeutic option. It is classified by the Biopharmaceutical Classification System (BCS) as a class II drug, that is, it is poorly water soluble and highly permeable [2]. Several approaches to improve the solubility of efavirenz are reported, from the manipulation of polymorphs [2] and blending with superdisintegrants [3] or into solid dispersions [4,5], to a broad variety of encapsulation strategies, which include liposomes [6], micelles [7,8], lipidic nanoparticles [9,10], and polymeric nanoparticles [11].

Molecular encapsulation of efavirenz with cyclodextrins is a less explored but quite promising solution for the amelioration of the physicochemical and organoleptic properties of this drug. Besides having low aqueous solubility, efavirenz presents a very bitter taste, and for this reason it may benefit from the taste-masking effect resulting from inclusion of each efavirenz molecule into the cavity of the cyclodextrin host. Cyclodextrins are cyclic oligosaccharides formed by natural or biotechnological enzymatic action on starch. The most abundant native cyclodextrins occur with six (α-CD), seven (β-CD), or eight (γ-CD, Figure 1a) D-glucose units, linked together by α-1,4 glycosidic bonds. The unique molecular geometry of cyclodextrins, with the shape of a truncated cone having the secondary hydroxyl groups facing the wider rim and the primary hydroxyls at the narrower rim, while the cavity is lined with protons, gives them hydrophobicity at the cavity in tandem with good aqueous solubility [12,13]. Cyclodextrins are thus used as

**Citation:** Braga, S.S.; El-Saleh, F.; Lysenko, K.; Paz, F.A.A. Inclusion Compound of Efavirenz and γ-Cyclodextrin: Solid State Studies and Effect on Solubility. *Molecules* **2021**, *26*, 519. https://doi.org/ 10.3390/molecules26030519

Academic Editors: Marina Isidori, Margherita Lavorgna and Rosa Iacovino Received: 30 December 2020 Accepted: 16 January 2021 Published: 20 January 2021

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biocompatible, solubilising, stabilising, and taste-masking agents for a variety of drugs [14], with highlight to the antiviral remdesivir [15] and to ozalin, a recently approved paediatric sedative and the only known commercial drug to contain γ-CD in its composition, acting as a solubiliser and taste-masking agent [16]. Cyclodextrins are gaining increased interest in medicinal applications, being employed as co-adjuvants in vaccines [17] or even as experimental drugs in disorders associated with lipid buildup, as Niemann–Pick disease or focal segmental glomerulosclerosis [18].

**Figure 1.** Chemical structure and atom labelling of (**a**) γ-cyclodextrin; (**b**) efavirenz.

Efavirenz is, thus far, only known to form inclusion complexes with two chemical derivatives of beta-cyclodextrin: HPβCD (randomly (2-hydroxy)propylated β-CD) and RAMEB (randomly methylated β-CD); inclusion into the native β-CD was also investigated but the formation of an authentic inclusion complex in the solid state was not demonstrated [19]. The study, conducted by Sathigari et al., further showed that the freeze-dried adducts with RAMEB and HPβCD increased efavirenz solubility in water (at 180 min) from 5.64 ± 1.149% (pure drug) to 54.25 ± 1.031% and 43.13 ± 0.331%, respectively. In a preliminary approach to the inclusion of efavirenz into native cyclodextrins, we investigated the possibility of using β-CD and γ-CD as hosts for efavirenz [20]. Efavirenz and each cyclodextrin were co-dissolved in a water/alcohol solution and the mixture was co-precipitated by cooling; in the batch of efavirenz with β-CD, the precipitate consisted of crystals of the two separate components [20], which confirmed that β-CD does not have adequate cavity size for efavirenz. Our results were, therefore, in good agreement with the findings of Sathigari et al. [19]. In the batch of efavirenz and γ-CD, a new, low-crystalline phase was formed, indicating the formation of an inclusion complex [20]. The preliminary findings on the formation of γ-CD·EFC prompted further investigation on this host-guest system, which is herein presented. Studies were conducted both in the aqueous solution phase and in the solid state. Results indicate the presence of a complex with 3:2 host–guest stoichiometry, in both the solution and solid phase.
