Crystal structures of vortioxetine and its methanol monosolvate

Vortioxetine, a new drug used to treat patients with major depressive disorder, has been crystallized as the free base and its methanol monosolvate. In both structures, the vortioxetine molecules have similar conformations.


Chemical context
Major depressive disorder (MDD) is a disabling mental illness responsible for almost 66 million disability-adjusted life-years globally (Bidzan et al., 2012). The medications most often prescribed for depression include the selective serotonin reuptake inhibitors (SSRIs) and the serotonin norepinephrine reuptake inhibitors (SNRIs). As several neurotransmitter pathways may be involved in MDD, antidepressants possessing two or more complementary modes of action (i.e. multimodal) have been a focus of MDD therapy for some time (Richelson, 2013). One such antidepressant is vortioxetine.
Vortioxetine is an investigational multi-modal antidepressant that is believed to work through a combination of two pharmacological modes of action: serotonin (5-HT) reuptake inhibition and 5-HT receptor activity (du Jardin et al., 2014;Hussar et al., 2014). In 2013, vortioxetine hydrobromide was approved by the US Food and Drug Administration (FDA) for the once-daily treatment of adults with MDD in the USA (Gibb & Deeks, 2014. The patent of Benny et al. (2007) discloses crystalline vortioxetine base and a variety of crys-talline vortioxetine salts, comprising polymorphs of vortioxetine hydrobromide as well as a hemihydrate and an ethyl acetate solvate thereof, and crystalline vortioxetine hydrochloride and a monohydrate thereof. Crystalline vortioxetine mesylate, mesohydrogentartrate, hydrogenmaleate and hydrogen sulfate are also disclosed. However, there are few reports on the single-crystal X-ray structure of vortioxetine base and its salts. As part of our ongoing structural studies of pharmaceutical compounds, the crystal structures of vortioxetine free base (1), and its methanol solvate (2), have been determined and reported here.

Structural commentary
The asymmetric unit of (1) consists of one vortioxetine molecule and that of compound (2) consists of one vortioxetine molecule and one methanol molecule. Views of the asymmetric units of (1) and (2), with atom labelling, are presented in Figs. 1 and 2, respectively. In both structures, the two benzene rings bridged by the S atom, are almost perpendicular to one another. The dihedral angles between the planes of these benzene rings is 80.04 (16) in compound (1) and 84.94 (13) in compound(2). The S atom is nearly coplanar with the benzene rings as indicated by C1-S1-C9-C14 torsion angles of 176.0 (2) for (1) and À176.04 (18) for (2).
The piperazine ring of both structures adopts a chair conformation with the exocyclic N1-C14 bond in a pseudo equatorial orientation. Atoms N1 and N2 deviate from the best fit plane through the remaining four C atoms by 0.683 (1) and 0.637 (1) Å in (1) and by 0.698 (1) and À0.562 Å in (2).

Supramolecular features
There are no hydrogen bonds orstacking interactions linking the molecules in (1), while in (2) the presence of the additional methanol solvent molecule results in the formation of zigzag chains mediated by alternating O1-H1Á Á ÁN2 and N2-H2AÁ Á ÁO1 i [symmetry code: (i) x, Ày + 1 2 , z + 1 2 ] hydrogen bonds propagating along the c-axis direction (Table 1). a packing diagram for (2) is shown in Fig. 3.

Synthesis and crystallization
Vortioxetine was supplied by Zhejiang Jingxin Pharmaceutical Co., Ltd. Crystals of (1) and (2) suitable for X-ray diffraction were recrystallized by slow evaporation from acetonitrile and methanol-water solutions, respectively, at room temperature over a few days.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. All H atoms were placed in idealized positions and refined as riding, with C-H = 0.93-0.97, N-H = 0.86 and O-H = 0.82 Å and U iso (H) = 1.2U eq or 1.5U eq (carrier atom). The molecular structure of compound (1), showing 50% probability displacement ellipsoids.

Special details
Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes. Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > σ(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.