Capecitabine from X-ray powder synchrotron data (2024)

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Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536809017905/cv2544sup1.cif

Rietveld powder data: contains datablocks I. DOI: 10.1107/S1600536809017905/cv2544Isup2.rtv

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Comment

Capecitabine is the first FDA-approved oral chemotherapy for the treatment forsome types of cancer, including advanced bowel cancer or breast cancer(Wagstaff et al., 2003; Jones et al., 2004).Capecitabineis5-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine and in vivo isenzymatically converted to the active drug 5-fluorouracil. Crystal structuredetermination of capecitabine was not reported yet. In this paper we reportcrystal structure determination of the title compound from the powderdiffraction data by using synchrotron radiation.

The asymmetric unit consists of one molecule of capecitabine (Fig 1). Thecrystal packing is stabilized by intermolecular interactions -electrostatic interactions proved by short O···C and F···C contacts (Table 1)and N—H···O hydrogen bonds (Table 2).

Experimental

Samples of crystalline capecitabine were prepared by two methods,a and b, respectively. Method a:capecitabine (10 g) was dissolved in EtOH (80 g). The solution wasconcentrated under reduced pressure to a residual volume of 25 ml and keptunder stirring overnight. The solid was filtered off and dried at roomtemperature furnishing capecitabine (6 g).Method b: capecitabine (18 g) wasdissolved in DCM (200 g) and the solution was evaporated to dryness underreduced pressure. The residue was taken up with toluene (400 g) and about 150 g of solvent were distilled off. The solution was heated up to 50°C and thenallowed to 3 spontaneously cool to 25°C. After cooling to 0°C, the solid wasfiltered off, washed with toluene and dried at 60°C under vacuum to constantweight furnishing capecitabine (16.5 g).

Refinement

Both crystallization procedures lead to one polycrystalline form ofcapecitabine. It was confirmed by measuring on X-Ray powder diffractometerPANalytical Xpert Pro, Cu Kα radiation (λ = 1.541874 Å). Attemptsto determine the structure from these data were unsuccessful probably due toflexible molecule of capecitabine and low resolution of these data. The powderobtained by the first "a" procedure was used for structure determination.X-Ray diffraction data were collected on the high resolution diffractometerID31 of the European Synchrotron Radiation Facility. The monochromaticwavelength was fixed at 0.79483(4) Å. Si (111) crystal multi-analysercombined with Si (111) monochromator was used (beam offset angle α = 2°). Arotating 1-mm-diameter borosilicate glass capillary with capecitabine powderwas used for the experiment. Data were measured from 1.002°2θ to 34.998°2θat the room temperature, steps scans was set to 0.003°2θ.

First 20 peaks were used by CRYSFIRE 2004 package (Shirley, 2000) toget a listof possible lattice parameters. The most probable result was selected(a = 5.21 Å, b = 9.52 Å, c = 34.79 Å, V = 1724 Å3, FOM (20) = 330). If 15 ų are used as an atomic volume for C, N, Oand F and 5 Å3 as a volume for hydrogen atom, the approximate molecularvolume is 485 ų. The found volume of 1724 ų suggests that there arefour molecules in the unit cell (Z = 4). P2₁2₁2₁ spacegroup was selected on the basic of peaks extinction and on the basic ofa*greement of the Le-bail fit. The structure was solved in program FOX(Favre-Nicolin & Černý, 2002) using parallel tempering algorithm.The initialmodel was generated by AM1 computing method implemented in program MOPAC(Dewar et al., 1985). For the solution process hydrogen atomswereremoved. This model was restrained with bonds and angles restraints,automatically generated by program FOX. The refinement was carried out inGSAS (Larson & Von Dreele, 1994). Hydrogen atoms were added inpositions based on geometry and structure was restrained by bonds and anglesrestraints. Five planar restraints for sp² hybridization were used(O20/C18/O19/N17, N17/C13/N14/C12, C13/C12/F16/C11, N14/C10/O15/N9 andC4/N9/C10/C11). Due to relatively high U_iso thermal parameters ofalkyl chain (C21—C25) the structure was refined with two disordered chains(C21—C25 and C21a—C25a) with occupancy factors 0.53(5) and0.47(5). U_iso thermal parameters were constrained just for atoms indisordered chains by this way (C21/C21a, C22/C22a,C23/C23a, C24/C24a, C25/C25a). At the final stage atomiccoordinates of non-hydrogen atoms were refined to the final agreement factors:R_p=0.055 and R_wp=0.0743. The diffraction profiles and thedifferences between the measured and calculated profiles are shown in Fig. 2.

Figures

Crystal data

Data collection

Refinement

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

Geometric parameters (Å, °)

Symmetry codes: (i) x−1, y, z; (ii) −x+1, y+1/2, −z+3/2; (iii) −x, y−1/2, −z+3/2.

Hydrogen-bond geometry (Å, °)

Symmetry codes: (ii) −x+1, y+1/2, −z+3/2.

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: CV2544).

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