Lamotrigine ethanol monosolvate

The main motif within the structure is a lamotrigine dimer stabilized by two ethanol molecules. Here the lamotrigine dimer forms using amines in the ortho position of the triazine group.

Lamotrigine is an active pharmaceutical ingredient used as a treatment for epilepsy and psychiatric disorders. Single crystals of an ethanolate solvate, C 9 H 7 Cl 2 N 5 ÁC 2 H 5 OH, were produced by slow evaporation of a saturated solution from anhydrous ethanol. Within the crystal structure, the lamotrigine molecules form dimers through N-HÁ Á ÁN hydrogen bonds involving the amine N atoms in the ortho position of the triazine group. These dimers are linked into a tape motif through hydrogen bonds involving the amine N atoms in the para position. The ethanol and lamotrigine are present in a 1:1 ratio in the lattice with the ethyl group of the ethanol molecule exhibiting disorder with an occupancy ratio of 0.516 (14):0.484 (14).

Chemical context
Anticonvulsants are a group of drugs used principally in the treatment of epilepsy, which have also been shown to aid in the treatment of psychiatric conditions such as bipolar disorder. Although the drugs are effective when inside the body, many suffer from having low solubility and bioavailability. Prime examples of such drugs are carbamazepine (Uzunović et al., 2010), phenytoin (Widanapathirana et al., 2015) and lamotrigine (Vaithianathan et al., 2015), which are all categorised as BCS (biopharmaceutical classification system) class II (low solubility, high permeability).
In an attempt to increase the solubility of BCS class II drugs, extensive studies have been undertaken to produce crystal structures including the active pharmaceutical ingredients (APIs) with lower crystal lattice energies. In the case of lamotrigine, Cheney et al. (2010) investigated the solubility of 10 novel forms, including salts, co-crystals and solvates, showing the possibility of creating many stable lamotrigine compounds. The structures of lamotrigine co-crystals and solvates are stabilized due to the large number of hydrogen bonds that can form with the 1,2,4-triazine-3,5-diamine group.
In this work, the structure for the ethanolate (I), previously only obtained as a powder pattern (Garti et al., 2008), is defined. This new structure determination affords a deeper ISSN 2056-9890 insight into the different hydrogen-bonding networks that can form in the lamotrigine crystal.

Structural commentary
A displacement ellipsoid plot for lamotrigine ethanolate is shown in Fig. 1. The central dihedral, C1-C6-C7-C8, sits at an angle of 63.5 (9) , the flexibility of which allows for the inclusion of solvent molecules to form hydrogen-bonding networks. Central dihedral angles for lamotrigine solvates are included in Table 1. Fig. 2 shows the unit cell for (I), which consists of eight lamotrigine molecules and eight ethanol molecules. The main motif within the structure is a lamotrigine dimer stabilized by two ethanol molecules. Here the lamotrigine dimer forms using the amine N atoms in the ortho position of the triazine group.

Supramolecular features
In the crystal, adjacent in-plane lamotrigine dimers are linked via hydrogen bonding of the amines in the para position of the triazine group (Table 2). Each dimer sits at an angle of 67.2 (5) to the next closest dimer, measured with respect to the in-plane triazine rings, highlighted in Fig. 3.

Figure 2
The crystal packing of (I), viewed along the c axis.

Figure 1
A displacement ellipsoid plot of (I), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level.

Figure 3
The bonding motif of adjacent lamotrigine dimers. The angle between the dimers was calculated using the planes of the indicated triazine rings.
the dimer formation of the lamotrigine molecules using the amine N atoms in the para position, shown in Fig. 4. This change in dimerization motif leads to a reduction in density of the lamotrigine ethanolate over the lamotrigine ethanol monohydrate by 5%. Analysis of the previously published lamotrigine alcohol solvates shows a trend between the alcohol chain length and whether the lamotrigine dimers form on the ortho or para group of the triazine. The two densest structures are the methanol disolvate (Hanna et al., 2009) and the ethanol solvate monohydrate, where lamotrigine dimers are connected via the amines in the para position of the triazine. Conversely, the methanol monosolvate (Janes et al., 1989), isopropanol solvate (Qian et al., 2009) and title compound form dimers from the amine on the ortho positions. The least dense structure is the butan-1-ol solvate monohydrate (Sridhar & Ravikumar, 2011), which has similar arrangement to the dense structures, with the dimers held apart by the large butanol solvent molecules. The densities of the lamotrigine structures are highlighted in Table 1.

Synthesis and crystallization
Lamotrigine (>98%, Acros Organics) was saturated in a solution of pure anhydrous ethanol (>99.5%, Sigma Aldrich) over several weeks. Crystals of lamotrigine ethanolate were produced via slow evaporation of 1 ml of the solution over 72 h.

Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. Refinement. The occupancies of the disordered atoms in the ethanol were refined with their sum set to equal 1. Restraints were applied to maintain sensible thermal and geometric parameters. The diffraction data showed slight splitting of some peaks but twinning could not be sensibly separated and modelled. However this may explain the large K values, slightly high second weight paramater and Fobs greater than Fcalc.