Crystal structure of 7-phenyl-7-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)heptanoate 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium monohydrate: a new solid form of seratrodast

In the title compound, seratrodast has crystallized with trometamol to form a monohydrated salt. The carboxylic acid group of seratrodast has transferred its proton to the amino N atom of trometamol.


Chemical context
Seratrodast is the first thromboxane A2 receptor antagonist to have been developed as an anti-asthmatic drug (Samara, 1996). This drug molecule with a carboxylic group is practically insoluble in water. Its new solid forms have been scarcely exploited and only a polymorphic transition was ever investigated (Urakami & Beezer, 2003). Tris(hydroxymethyl)amino methane, commonly called trometamol, is often used as a buffer in biochemical studies. It has been successfully exploited for improving properties of APIs such as ketoprofen (Zippel & Wagenitz, 2006). In this study, trometamol was employed to co-crystallize with seratrodast to give rise to a hydrated salt. To the best of our knowledge, the title salt is the first multi-component crystalline form of seratrodast to be reported.

Structural commentary
The molecular structure of the title salt is illustrated in Fig. 1. It was clear from a difference Fourier map that the carboxylic group of seratrodast had transferred its proton to the amino N atom of trometamol. The bond distances C1-O1 and C1-O2

Supramolecular features
In the crystal, the trometamol cations are linked to the water molecules and to each other by N-HÁ Á ÁO and O-HÁ Á ÁO hydrogen bonds, forming sheets parallel to (100); see Table 1 and Fig. 2. The seratrodast anions are linked to both sides of these sheets by O-HÁ Á ÁO and C-HÁ Á ÁO hydrogen bonds, forming a three-layer two-dimensional structure ( Fig. 3 and Table 1). Further details of the hydrogen bonding are given below and in Table 1 . Along the c axis, the R 2 2 (11) heterosynthon gives rise to a hydrogen-bonded chain of trometamol cations, which is further linked into a twodimensional structure by hydrogen-bonding interactions between the amino and the hydroxyl groups [N1Á Á ÁO5 ii = 2.935 (3) Å ]. There also exist hydrogen-bonding interactions between water and trometamol [N1Á Á ÁO8 i = 2.800 (4) Å ; O7Á Á ÁO8 iii = 2.686 (3) Å ]. The various hydrogen-bonding interactions result in a two-dimensional layer structure in which the seratrodast anions are spread around two sides of the layer in an orderly manner (Table 1 and Fig. 3).

Database survey
To the best of our knowledge, the title salt is the first multicomponent crystalline form of seratrodast to be reported. A view along the c axis of the crystal packing of the title compound (hydrogen bonds are shown as dashed lines; see Table 1 for details). H atoms not involved in hydrogen bonding have been omitted for clarity A view of the molecular structure of the title salt, with atom labelling. Displacement ellipsoids are drawn at the 50% probability level. Hydrogen bonds are shown as dashed lines (see Table 1 for details).

Synthesis and crystallization
Seratrodast (354 mg, 1 mmol) and trometamol (121 mg, 1 mmol) were dissolved in methanol (15 ml). The resulting solution was kept in air and after several days yellow blocklike crystals of the title salt were obtained.

Solubility Studies
Excess amounts of seratrodast and the title salt were suspended in 10 ml of water in screw-capped glass vials, respectively. These vials were kept at 310 K and were stirred at 100 r.p.m. using a magnetic stirrer. After 72 h, the suspensions were filtered through a 0.2 mm syringe filter. The filtered aliquots were sufficiently diluted, and the absorbances were measured at 268 nm in triplicate. Finally, the concentration of seratrodast after 72 h in each sample was determined from the previously made standard graph. A standard graph was made by measuring the absorbance of varied concentrations of seratrodast (2-16 mg/L) in water/methanol (9:1) solution using a UV-2500 spectrophotometer at 268 nm. The calibrated plot showed a good correlation coefficient (y = 0.04997x + 0.00459, R 2 = 0.9991). After forming the title salt, the solubility of seratrodast was found to be greatly improved.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. The C-bound H atoms were positioned geometrically and refined as riding atoms: C-H = 0.95-1.00 Å with U iso (H) = 1.2U eq (C). The OH and NH 3 + H atoms were located in difference Fourier maps and refined as riding atoms with U iso (H) = 1.2U eq (O,N).    Data collection: CrystalClear (Rigaku, 2000); cell refinement: CrystalClear (Rigaku, 2000); data reduction: CrystalClear (Rigaku, 2000); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: Mercury (Macrae et al., 2008); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008), PLATON (Spek, 2009) and publCIF (Westrip, 2010). where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.55 e Å −3 Δρ min = −0.42 e Å −3 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.