Clarithromycin monohydrate: a synchrotron X-ray powder study

In the crystal structure of the title compound, clarithromycin (CAM) monohydrate, C38H69NO13·H2O, the water molecule behaves as a proton donor and is hydrogen bonded to the hydroxy O atom of the CAM cladinose ring. The hydroxy O atom also behaves as a proton donor, forming an intermolecular hydrogen bond with one of the hydroxy groups of the 14-membered aglycone ring. The CAM molecules are linked through these hydrogen bonds into chains running parallel to the c axis.

In the crystal structure of the title compound, clarithromycin (CAM) monohydrate, C 38 H 69 NO 13 ÁH 2 O, the water molecule behaves as a proton donor and is hydrogen bonded to the hydroxy O atom of the CAM cladinose ring. The hydroxy O atom also behaves as a proton donor, forming an intermolecular hydrogen bond with one of the hydroxy groups of the 14-membered aglycone ring. The CAM molecules are linked through these hydrogen bonds into chains running parallel to the c axis.

Related literature
For background to the title compound, see Avrutov et al. (2003); Noguchi, Fujiki et al. (2012). For information relating to the pharmaceutical properties of CAM, see: Yajima et al. (1999Yajima et al. ( , 2002; Fujiki et al. (2011);Liu et al. (1999).   Table 1 Hydrogen-bond geometry (Å , ). This study was partly supported by a grant from the Pharmaceutical and Medical Device Regulatory Science Society of organic compounds stable anhydrate form II in the treatment of infections caused by bacteria (Yajima et al., 1999(Yajima et al., , 2002Fujiki et al., 2011).
Another anhydrate crystal form of CAM, metastable form I, has a dissolution rate three times greater than that of form II (Liu et al., 1999), indicating its potential use for a new drug formulation. We recently found that CAM form I spontaneously transforms to CAM monohydrate form IV when stored under high-humidity conditions at room temperature (Noguchi, Fujiki et al., 2012). Although existence of form IV has been documented in the literature (Avrutov et al., 2003), its structure remains unknown. As form IV is believed to be a possible impurity of form I, crystallographic characterization of form IV is necessary to enable a new drug formulation using form I to progress into practical use. We report here the crystal structure of form IV as determined by synchrotron powder X-ray diffraction analysis. The asymmetric unit of form IV contains one CAM molecule and one water molecule. The O14 atom of the water molecule behaves as a proton donor and is hydrogen-bonded to the hydroxy O12 atom of the CAM cladinose ring. Furthermore, the hydroxy O12 atom acts as a proton acceptor, forming an intermolecular hydrogen bond with the hydroxy O6 i atom of CAM aglycone ring (symmetry code in Table 1). Through this intermolecular O6 i -O12 hydrogen bonding interaction, CAM molecules are linked into chains running parallel to the c axis, as shown in Fig. 2.

Experimental
Powders of CAM form I were prepared as described (Noguchi, Miura et al., 2012) and were converted to form IV by storing at greater than 90% relative humidity overnight in a hermetic glass container at 297 K. Relative humidity was measured by digital hygrometer AD-5683 (A&D, Tokyo, Japan). The powders of form IV thus obtained were enclosed in a 0.3 mm Lindemann glass capillary. The powder diffraction data were collected at SPring-8 BL19B2 (Osaka et al., 2010;Takata et al., 2002). The sample was rotated at 1 r min -1 to reduce the possible preferential orientation and was kept at 298 K.

Refinement
The determination of cell parameters and space group and the extraction of the Bragg peak intensities from the powder diffraction data were carried out using EXPO2009. The initial structure was determined by the molecular replacement method using MOLREP implemented in CCP4. The search model employed was form 0 of the CAM crystal structure (Jin et al., 2011). All H atoms were excluded from the model and the isotropic atomic displacement parameters were fixed at a value of 0.089 Å 2 . Reflections between 12.1 and 2.50 Å d-spacings were used for the calculation. The structure solution of the molecular replacement was refined using REFMAC implemented in CCP4. The bond lengths and bond angles were restrained to those of the form 0 crystal structure. The crystallographic R factor converged at 0.245. In the difference Fourier map, the positive spherical density was found at a distance of approximately 2.7 Å from the hydroxy supplementary materials O12 atom of the CAM cladinose ring. The O atom of the water molecule was placed at this density and the model was further refined, resulting in the convergence of the R factor at 0.201. This partially refined structure provided the starting model for Rietveld refinement. The geometry of the CAM molecule was restrained as described above. H atoms were placed at their theoretical positions using EXPO2009 and Jmol and were refined as riding. The overall atomic displacement parameter was applied to all atoms including H atoms, and was refined isotropically. The observed and Rietveld refined calculated powder patterns are shown in Fig. 3. The r.m.s differences of the bond lengths and angles from their target values were 0.023 Å and 2.7 °, respectively.   Packing view of CAM. The molecular chains generated by hydrogen bonding between CAM molecules along the c axis are coloured as in Fig. 1. [Symmetry code: (i) x, y, z -1, (ii) x, y, z + 1.] Molecules of symmetry codes (iii) x + 1/2, -y + 1/2, -z + 1, (iv) -x + 1/2, -y + 1, z + 1/2, and (v) -x + 1, y + 1/2, -z + 1/2 are shown in light green, light blue and cyan, respectively.