Crystal structures of anhydrous and hydrated ceftibuten

The crystal structures of anhydrous and hydrated ceftibuten are reported. Both crystallize as zwitterions.


Chemical context
Ceftibuten, originally marketed under the tradename Cedax in the USA, is a third-generation cephalosporin antibiotic with activity against a variety of bacterial strains and resistance to extended spectrum -lactamases (Wiseman & Balfour, 1994;Hamashima et al., 1990). Oral administration of ceftibuten is effective for treating urinary tract or respiratory tract infections, including many caused by -lactamase-expressing bacterial strains (Owens et al., 1997). Despite its withdrawal from the US market, because of its effectiveness and stability against -lactamases, renewed interest in ceftibuten for multidrug-resistant urinary tract infections (UTIs) has emerged, and studies are underway investigating oral administration of ceftibuten co-administered with a -lactamase inhibitor as an alternative to hospitalization for complicated UTIs (Veeraraghavan et al., 2021;Chatwin et al., 2021).
Despite its long-time commercial availability, to our knowledge no crystal structures of ceftibuten have been previously reported. The structures of anhydrous ceftibuten (I) and hydrated ceftibuten (II) are reported herein.

Structural commentary
The anhydrous compound (I) (Fig. 1) has the formula C 15 H 14 N 4 O 6 S 2 and crystallizes in the orthorhombic space group P2 1 2 1 2 1 . The asymmetric unit of (I) contains one molecule of ceftibuten: the chiral C8 and C12 centers both have an absolute configuration of R. This is reflected in the N13-C12-C8-S7 torsion angle of 5.0 (10) . The C24-C25-O26-O27 atoms were treated as disordered over two adjacent sets of sites with a population ratio of 0.841 (11): 0.159 (11). The -lactam ring is almost planar with the C8/C12/ C10/N9 atoms in the ring having a calculated r.m.s. deviation of 0.032 Å . Based on the refined bond distances of C3-O1 = 1.258 (9) Å and C3-O2 = 1.254 (9) Å , we have assigned the O1-O2-C3 group as a carboxylate and the N22 atom of the thiazole ring as protonated based on peaks in the residual electron density map, i.e., the molecule exists as a zwitterion in the solid state.
The hydrated compound (II) (Fig. 2) has the formula C 15 H 14 N 4 O 6 S 2 Á2.7H 2 O and crystallizes in the orthorhombic space group P2 1 2 1 2 1 with similar unit-cell parameters to (I). The asymmetric unit of (II) includes one ceftibuten molecule, one fully occupied O31 water molecule, and two partially occupied O32 and O33 water molecules, which were independently refined to occupancies of 0.828 (10) and 0.824 (12), respectively. The chiral C8 and C12 centers both have an absolute configuration of R and N13-C12-C8-S7 = 17.2 (4) . The -lactam ring is slightly buckled in (II) compared to (I), with the atoms in the ring having a calculated r.m.s. deviation of 0.078 Å . As in (I), we have assigned the O1-C3-O2 group as a carboxylate anion based on bond distances of C3-O1 = 1.252 (4) Å and C3-O2 = 1.256 (4) Å and the N22 atom as protonated based on peaks in the residual electron-density map.

Supramolecular features
The extended structure of (I) displays a three-dimensional hydrogen-bonding network with O-HÁ Á ÁO and N-HÁ Á ÁO hydrogen bonds linking adjacent ceftibuten molecules ( Molecular structure of (II). Ellipsoids of non-H elements are drawn at 50% probability.
unit cell of about 42 Å 3 each (total void volume = 167.3 Å 3 ), which account for 9.2% of the unit-cell volume, as calculated in PLATON (Spek, 2020). The void spaces form channels propagating along the [100] direction (Fig. 3). The layers of ceftibuten molecules are linked along the a-axis direction by N-HÁ Á ÁO hydrogen bonds. Two weak C-HÁ Á ÁO interactions are also present. Compound (II) displays a three-dimensional hydrogenbonding network composed of O-HÁ Á ÁO and N-HÁ Á ÁO hydrogen bonds between ceftibuten molecules, O-HÁ Á ÁO and N-HÁ Á ÁO hydrogen bonds between ceftibuten and the free water molecules, and O-HÁ Á ÁO hydrogen bonds between the free water molecules (Table 2). Four weak C-HÁ Á ÁO bonds occur. The O32 and O33 water molecules occupy the channel void space that is present in (I) (Fig. 4). A previous study examined the structures of 32 known water-containing -lactams (Hickey et al., 2007). Following the system of Gillon et al. (2003), the authors describe three distinct hydrogen-bonding motifs in hydrated -lactam compounds based on the donor/acceptor roles of the water molecules in hydrogen bonds. The O31 water molecule in (II) acts as a donor in two hydrogen bonds and acceptor in two hydrogen bonds, meaning that the hydrogen-bonding behavior of the O31 water molecule in (II) can be classified as 'environment C 0 . In contrast, the O32 and O33 water molecules can be assigned environment B based on their participation as donors in two hydrogen bonds and as acceptors in one hydrogen bond.

Synthesis and crystallization
Ceftibuten hydrate was purchased from ACS Dobfar (Tribiano, Italy). Dehydration occurs following exposure to an atmosphere below 30% relative humidity at 298 K, and the material was confirmed to be anhydrous following receipt at the University of South Florida X-Ray Facility. A crystal in the  Table 2 Hydrogen-bond geometry (Å , ) for (II).

Figure 4
Packing diagram of (II). Non-water H atoms are omitted for clarity.

Figure 3
Packing diagram of (I). Void spaces are shown in orange. Hydrogen atoms are omitted for clarity.
form of a colorless needle was selected directly from the bulk sample (I) and deemed suitable for analysis. For rehydration, ceftibuten powder was placed in an uncapped scintillation vial within a container of pure water. The sealed container was stored at room temperature for four weeks, and a sufficiently large crystal (a colorless needle) was selected for analysis.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. The N-H and O-H hydrogen positions were assigned from residual electron density peaks and refined with distances constrained. All remaining hydrogen atoms were assigned with a riding model. The C24-C25-O26-O27 atoms in (I) were treated as disordered with a population ratio of approximately 80:20 and refined with restrained interatomic distances. The occupancies of the O32 and O33 water molecules in (II) were freely refined.
Acta Cryst. (2022). E78, 381-384 research communications   For both structures, data collection: SAINT (Bruker, 2016); cell refinement: SAINT (Bruker, 2016); data reduction: SAINT (Bruker, 2016); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL (Sheldrick, 2015b); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).  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.