**1. Introduction**

The generation of a new salt form is a proven way to modify the physical and chemical properties of an active pharmaceutical ingredient (API) [1]. To be able to give rise to a new salt form, however, the API in question should be ionizable. For non-ionizable APIs, co-crystallization with a crystallophoric excipient (non-API component of the solid drug form) has become an alternative, proven way of accessing a broad range of solid forms and thus modifying various physicochemical properties and increasing API's stability [2–4]. An overwhelming majority of API co-crystals reported today are based on hydrogen bonding as the principal means of constructing the crystalline form. However, halogen bonds have emerged as an equally promising basis for designing new co-crystalline API forms [5–12]. However, despite the emergence of this intriguing supramolecular interaction, halogen-bonded API co-crystals remain relatively scarce. This may have to do with the limited range of pharmaceutically acceptable excipients containing polarized halogen atoms [13]. In continuation of our efforts to identify new crystalline forms for APIs that would be stabilized by halogen bonding [14,15], we turned our attention to screening of crystallization conditions for the title compound, anastrozole (IUPAC name 2,2<sup>0</sup> -(5-((1H-1,2,4-triazol-1-yl)methyl)-1,3-phenylene)bis(2-methylpropanenitrile), abbreviated as ASZ), which is an aromatase inhibitor useful in second-line therapy of estrogen-dependent breast cancer [16–18].

We choose this API as a potential recipient of XB due to its 1,2,4-triazole moiety, containing at least two nucleophilic Nsp2 atoms as potential XB acceptor centers. One of them is a hydrogen bond [19] (HB) acceptor in the crystal structure of ASZ itself (Figure 1) [20]. We choose this API as a potential recipient of XB due to its 1,2,4-triazole moiety, containing at least two nucleophilic Nsp2 atoms as potential XB acceptor centers. One of them is a hydrogen bond [19] (HB) acceptor in the crystal structure of ASZ itself (Figure 1) [20].

*Crystals* **2020**, *10*, 371 2 of 13

**Figure 1.** Structure of anastrozole with assigned hydrogen bond donor (red) and hydrogen bond acceptor centers (blue) found in its crystal structure (SATHOL) [20]. **Figure 1.** Structure of anastrozole with assigned hydrogen bond donor (red) and hydrogen bond acceptor centers (blue) found in its crystal structure (SATHOL) [20].

Previously, we successfully cocrystallized another API, nevirapine, with classic XB donor, 1,2,4,5-tetrafluoro-3,6-diiodobenzene (also known as 1,4-diiodotetrafluorobenzene, **1,4-FIB**). Noticeably, **1,4-FIB** has already been employed in the co-crystal formation for a number of biologically active compounds including nicotine [21], pyrazinamide, lidocaine, and pentoxifylline [22]. It should be noted, however, that in these studies (as well as in present work), **1,4-FIB** is employed as an exploratory co-crystallization partner. For its use as an excipient for the design of solid drug forms, a further clinical investigation will be required. In this work, we found ASZ can also be cocrystallized with **1,4-FIB** from their solution in MeOH, forming the 2:3 adduct. Herein, we present the results of combined single-crystal XRD experimental and theoretical studies of the adduct and noncovalent interactions found in it. Previously, we successfully cocrystallized another API, nevirapine, with classic XB donor, 1,2,4,5-tetrafluoro-3,6-diiodobenzene (also known as 1,4-diiodotetrafluorobenzene, **1,4-FIB**). Noticeably, **1,4-FIB** has already been employed in the co-crystal formation for a number of biologically active compounds including nicotine [21], pyrazinamide, lidocaine, and pentoxifylline [22]. It should be noted, however, that in these studies (as well as in present work), **1,4-FIB** is employed as an exploratory co-crystallization partner. For its use as an excipient for the design of solid drug forms, a further clinical investigation will be required. In this work, we found ASZ can also be cocrystallized with **1,4-FIB** from their solution in MeOH, forming the 2:3 adduct. Herein, we present the results of combined single-crystal XRD experimental and theoretical studies of the adduct and noncovalent interactions found in it.

#### **2. Materials and Methods 2. Materials and Methods**

### *2.1. Materials 2.1. Materials*

Anastrozole, 1,2,4,5-tetrafluoro-3,6-diiodobenzene, and MeOH were obtained from a commercial source and used as received. Anastrozole, 1,2,4,5-tetrafluoro-3,6-diiodobenzene, and MeOH were obtained from a commercial source and used as received.
