Crystal structure of an apremilast ethanol hemisolvate hemihydrate solvatomorph

The title compound represents another solvatomorph of apremilast, containing half of an ethanol and half of a water solvent molecule per formula unit

The title compound, C 22 H 24 N 2 O 7 SÁ0.5C 2 H 5 OHÁ0.5H 2 O {systematic name: (S)-4-acetamido-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindoline-1,3-dione ethanol hemisolvate hemihydrate}, is a novel solvatomorph of apremilast (AP), which is an inhibitor of phosphodiesterase 4 (PDE4) and is indicated for the treatment of adult patients with active psoriatic arthritis. The asymmetric unit contains one molecule of AP and disordered molecules of ethanol and water, both with half occupancy. The dihedral angle between the planes of the phenyl ring and the isoindole ring is 67.9 (2) . Extensive intra-and intermolecular hydrogen bonds help to stabilize the molecular conformation and sustain the crystal packing.

Chemical context
Analogues of thalidomide have been reported to possibly enhance tumor necrosis factor alpha (TNF) inhibitory activity Muller et al., 1996) and phosphodiesterase type 4 (PD4) inhibition (Muller et al., 1998), hence showing potential for the treatment of inflammatory diseases (de Brito et al., 1997). Among these substances are phenethylsulfones substituted in the position to the phenyl group with a 1-oxoisoindoline or 1,3-dioxoisoindoline group that can reduce the levels of TNF in a mammal. Typical embodiments are (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4-acetamidoisoindoline-1,3-dione] with the generic name apremilast (AP), which is an inhibitor of phosphodiesterase 4 (PDE4) and is indicated for the treatment of adult patients with active psoriatic arthritis (Gottlieb et al., 2008;Man et al., 2009;Duplantier et al., 1996). In our previous studies, we reported three solvatomorphs of AP with ethyl acetate, toluene and dichloromethane, respectively (Wu et al., 2017). However, these three solvates exhibit toxicity, in particular the solvates of toluene and dichloromethane, which clearly limits the possibility of these compounds being developed into drugs. In a continuation of our work, a novel solvatomorph of AP with ethanol and water solvents in the molar ratio 1:0.5:0.5 was prepared and its crystal structure determined. This solvatomorph of AP appears to be suitable for development into a powerful drug, showing much lower toxicity than the solvatomorphs of ethyl acetate, toluene and dichloromethane.

Structural commentary
The title solvatomorph (I) crystallizes in the same space group (P4 1 2 1 2) as the other three structurally characterized solvatomorphs of ethyl acetate, toluene and dichloromethane (Wu et al., 2017). The structures of the molecular components of (I) are shown in Fig. 1. The asymmetric unit comprises one molecule of AP and one solvent molecule each of ethanol and water, both being disordered about a twofold rotation axis (occupancy for both solvent molecules = 0.5). A space-filling drawing of the structure is given in Fig. 2, emphasizing the positions of the solvent molecules in the crystal structure. The bond lengths and angles in the AP molecule are in normal ranges and very similar to those in the previous three solvatomorphs (Wu et al., 2017)  The unit cell of (I), with the solvent molecules shown in space-filling mode. [See Table 1 for symmetry codes.] Table 1 Hydrogen-bond geometry (Å , ). Symmetry codes: (i) y; x; Àz þ 1; (ii) x þ 1 2 ; Ày þ 3 2 ; Àz þ 3 4 ; (iii) Ày þ 5 2 ; x þ 1 2 ; z þ 1 4 ; (iv) Ày þ 3 2 ; x À 1 2 ; z þ 1 4 .

Figure 1
The structures of the molecular components in (I). Displacement ellipsoids are drawn at the 50% probability level. Hydrogen bonds are shown as dashed lines.
The water molecule (O9) is hydrogen-bonded to the AP molecule by C22-H22CÁ Á ÁO9 and O9-H9BÁ Á ÁO1 interactions and likewise is bonded by an O8-H8AÁ Á ÁO9 interaction to the ethanol solvent molecule. As well as these hydrogen bonds involving the solvent molecules, there are interactions between AP molecules. Two AP molecules are arranged into a dimer with an R 1 2 (7) motif ( Fig. 3) by C-HÁ Á ÁO hydrogen bonds, and a zipper-like chain including R 2 2 (18) motifs ( Fig. 4) is formed parallel to the a axis by additional C-HÁÁO hydrogen bonds.

Synthesis and crystallization
AP was prepared according to a literature protocol (Muller et al., 2006(Muller et al., , 2008a. A 100 ml round-bottomed flask equipped with a magnetic stirring bar was charged with a solution of (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethanamine N-acetyl leucine salt (5.0 g, 11.2 mmol, 1.0 eq) and 3-acetamidophthalic anhydride (2.42 g, 11.8 mmol, 1.05 eq) to which glacial acetic acid (50 ml) was added. The mixture was refluxed for 16 h and then cooled to room temperature. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The resulting solution was washed with water (2 Â 50 ml), saturated aqueous sodium bicarbonate (2 Â 50 ml), brine (2 Â 50 ml), and dried over anhydrous sodium sulfate. The solvents were evaporated in vacuo, and the obtained AP recrystallized from an ethanol/acetone mixture (2:1, v/v). Single crystals of (I) were obtained by slow evaporation of an AP-saturated solution from an N,N-dimethylformamide/ethanol/water mixture (1:10:2, v/v/v), at room temperature over 90 days.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. Hydrogen atoms bound to nitrogen or carbon atoms were placed in calculated positions (N-H = 0.87, C-H = 0.93-0.98 Å ) and constrained to ride on their carrier atoms [U iso (H) = 1.2U eq (C,N) or 1.5U eq (C methyl )].  (AP) 2 dimers with an R 1 Hydrogen atoms bound to oxygen atoms were deduced from difference-Fourier maps and their positions relative to donor and possible acceptor atoms. They were refined with U iso (H) = 1.5U eq (O). The solvent ethanol and water molecules are disordered about a twofold rotation axis and were refined with an occupancy of 0.5. To get reasonable shape and displacement parameters for both molecules, they were treated with DFIX, RIGU and ISOR restraints in SHELXL2014 (Sheldrick, 2015b). . E73, 821-824 research communications

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.