I. INTRODUCTION
Cefdinir (brand name Omnicef®) is a third-generation oral cephalosporin antibiotic used to treat bacterial infections of the ears, sinuses, throat, lungs, and skin. The IUPAC name (CAS Registry number 91832-40-5) is (6R,7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-hydroxyiminoacetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. A two-dimensional molecular diagram is shown in Figure 1.
The molecular structure of cefdinir.
The convoluted patent history of cefdinir and its polymorphs is described in Cabri et al. (Reference Cabri, Ghetti, Pozzi and Alpegiani2007). Several companies including ACS Dobfar (Manca et al., Reference Manca, Sala and Monguzzi2003), Fujisawa (Takaya et al., Reference Takaya, Takasugi, Magugi, Yamanaka and Kawabata1985; now Astellas), Ranbaxy (Kumar et al., Reference Kumar, Prasad and Prasad2004), Aurobindo (Dandala and Sivakumaran, Reference Dandala and Sivakumaran2005), Abbott (Law et al., Reference Law, Henry and Lou2005), and Lupin (Singh et al., Reference Singh, Sen, Srivastava, Godbole, Singh, Mahajan, Rananaware, Nehate and Wagh2005) have reported similar powder patterns for anhydrous cefdinir (Figure 2). Somewhat more variety has been reported for the powder patterns of cefdinir hydrates (Figure 3; Takaya et al., Reference Takaya, Takasugi, Magugi, Yamanaka and Kawabata1985; Manca et al., Reference Manca, Sala and Monguzzi2003; Chandrasekaran et al., Reference Chandrasekaran, Senthilkumar, Murugan, Siviah Sangaraju and Reddy2005; Law et al., Reference Law, Henry and Lou2005; Daemon et al., Reference Daemon, Hartmann and Raneburger2006). A low-precision pattern of a new form of cefdinir is included in PDF entry 00-067-0972 (Sun et al., Reference Sun, Liu and Feng2015).
(Color online) Simulated powder patterns of anhydrous cefdinir from Cabri et al. (Reference Cabri, Ghetti, Pozzi and Alpegiani2007). (a) Dobfar (Manca et al., Reference Manca, Sala and Monguzzi2003). (b) Fujisawa (Takaya et al., Reference Takaya, Takasugi, Magugi, Yamanaka and Kawabata1985). (c) Aurobindo (Dandala and Sivakumaran, Reference Dandala and Sivakumaran2005). (d) Abbott (Law et al., Reference Law, Henry and Lou2005). (e) Lupin (Singh et al., Reference Singh, Sen, Srivastava, Godbole, Singh, Mahajan, Rananaware, Nehate and Wagh2005).
(Color online) Simulated powder patterns of hydrated cefdinir from Cabri et al. (Reference Cabri, Ghetti, Pozzi and Alpegiani2007). (a) Dobfar (Manca et al., Reference Manca, Sala and Monguzzi2003). (b) Fujisawa (Takaya et al., Reference Takaya, Takasugi, Magugi, Yamanaka and Kawabata1985). (c) Abbott sesquihydrate (Law et al., Reference Law, Henry and Lou2005). (d) Abbott low water (Law et al., Reference Law, Henry and Lou2005). (e) Abbott anhydrous (Law et al., Reference Law, Henry and Lou2005). (f) Orchid (Chandrasekaran et al., Reference Chandrasekaran, Senthilkumar, Murugan, Siviah Sangaraju and Reddy2005). (g) Novartis (Singh et al., Reference Singh, Sen, Srivastava, Godbole, Singh, Mahajan, Rananaware, Nehate and Wagh2005).
This work was carried out as part of a project (Kaduk et al., Reference Kaduk, Crowder, Zhong, Fawcett and Suchomel2014) to determine the crystal structures of large-volume commercial pharmaceuticals, and include high-quality powder diffraction data for these pharmaceuticals in the Powder Diffraction File (Fawcett et al., Reference Fawcett, Kabekkodu, Blanton and Blanton2017).
II. EXPERIMENTAL AND STRUCTURE REFINEMENTS
Cefdinir and “cefdinir monohydrate” were commercial reagents, purchased from Sigma Aldrich (Lot #093M4817 V) and United States Pharmacopeia (Lot #G0K367) respectively, and were used as-received. The white powders were packed into 1.5 mm diameter Kapton capillaries, and rotated during the synchrotron diffraction experiment measurement at ~50 Hz. The powder patterns were measured at 295 K at beam line 11-BM (Lee et al., Reference Lee, Shu, Ramanathan, Preissner, Wang, Beno, Von Dreele, Ribaud, Kurtz, Antao, Jiao and Toby2008; Wang et al., Reference Wang, Toby, Lee, Ribaud, Antao, Kurtz, Ramanathan, Von Dreele and Beno2008) of the Advanced Photon Source at Argonne National Laboratory using wavelengths of 0.414157 (cefdinir) and 0.413342(cefdinir sesquihydrate) Å from 0.5–50° 2θ with a step size of 0.001° and a counting time of 0.1 s step−1.
A. Cefdinir
The pattern was indexed on a monoclinic unit cell with a = 5.35781, b = 19.86499, c = 7.57960 Å, β = 97.036°, V = 800.6 Å3, and Z = 2 using N-TREOR as incorporated into EXPO2014 (Altomare et al., Reference Altomare, Cuocci, Giacovazzo, Moliterni, Rizzi, Corriero and Falcicchio2013). Analysis of potential space groups suggested P2 1, which was confirmed by successful solution and refinement. A reduced cell search in the Cambridge Structural Database (Groom et al., Reference Groom, Bruno, Lightfoot and Ward2016) combined with the chemistry C, H, N, O, and S yielded one hit, but no crystal structure for cefdinir. The cefdinir molecule was built using Spartan “16 (Wavefunction, 2017) and saved as a mol2 file, which was converted into a Fenske-Hall Z-matrix using OpenBabel (O'Boyle et al., Reference O'Boyle, Banck, James, Morley, Vandermeersch and Hutchison2011). The structure was solved with FOX (Favre-Nicolin and Černý, Reference Favre-Nicolin and Černý2002).”
Rietveld refinement was carried out using GSAS (Toby, Reference Toby2001; Larson and Von Dreele, Reference Larson and Von Dreele2004). Only the 2.0–25.0° portion of the pattern was included in the refinement (d min = 0.957 Å). All non-H bond distances and angles were subjected to restraints, based on a Mercury/Mogul Geometry Check (Bruno et al., Reference Bruno, Cole, Kessler, Luo, Motherwell, Purkis, Smith, Taylor, Cooper, Harris and Orpen2004; Sykes et al., Reference Sykes, McCabe, Allen, Battle, Bruno and Wood2011) of the molecule. The Mogul average and standard deviation for each quantity were used as the restraint parameters. The restraints contributed 6.0% to the final χ 2. The hydrogen atoms were included in calculated positions, which were recalculated during the refinement using Materials Studio (Dassault, 2018). Positions of the active hydrogens were derived by analysis of potential hydrogen bonding patterns. A common U iso was refined for the non-H atoms of the fused-ring system, another U iso for the thiazole ring, another for the center of the molecule, another U iso for the carboxylic acid, and another U iso for the ethylene substituent. The U iso for each hydrogen atom was constrained to be 1.3 × that of the heavy atom to which it is attached. The peak profiles were described using profile function #4 (Thompson et al., Reference Thompson, Cox and Hastings1987; Finger et al., Reference Finger, Cox and Jephcoat1994), which includes the Stephens (Reference Stephens1999) anisotropic strain broadening model. The background was modeled using a 3-term shifted Chebyshev polynomial. A 4th-order spherical harmonic preferred orientation model was included in the refinement; the texture index was 1.0018, indicating that preferred orientation was not significant in this rotated capillary specimen.
The final refinement of 108 variables using 23 070 observations (23 001 data points and 69 restraints) yielded the residuals Rwp = 0.0582, Rp = 0.0471, and χ 2 = 1.711. The largest peak (1.80 Å from O26) and hole (1.94 Å from C32) in the difference Fourier map were 0.17 and −0.18 eÅ−3, respectively. The Rietveld plot is included as Figure 4. The largest errors in the fit are in the shapes of some of the strong, low angle peaks.
(Color online) The Rietveld plot for the refinement of anhydrous cefdinir. The black crosses represent the observed data points, and the red line is the calculated pattern. The blue curve is the difference plot, plotted at the same scale as the other patterns. The row of magenta tick marks indicates the calculated reflection positions. The vertical scale has been multiplied by a factor of 10 for 2θ > 12.8°.
A density functional geometry optimization (fixed experimental unit cell) was carried out using VASP (Kresse and Furthmüller, Reference Kresse and Furthmüller1996). The calculation used the GGA-PBE functional, a plane wave cutoff energy of 400.0 eV, and a k-point spacing of 0.5 Å−1 leading to a 6 × 6 × 1 mesh. The calculation was carried out on 16 2.4 GHz processors (each with 4 Gb RAM) of a 64-processor HP Proliant DL580 Generation 7 Linux cluster at North Central College, and took ~28 h. A density functional geometry optimization was also carried out using CRYSTAL14 (Dovesi et al., Reference Dovesi, Orlando, Erba, Zicovich-Wilson, Civalleri, Casassa, Maschio, Ferrabone, De La Pierre, D-Arco, Noël, Causà and Kirtman2014). The basis sets for the H, C, N, and O atoms were those of Gatti et al. (Reference Gatti, Saunders and Roetti1994), and the basis set for S was that of Bredow et al. (Reference Bredow, Heitjans and Wilkening2004). The calculation was run on eight 2.1 Ghz Xeon cores (each with 6 Gb RAM) of a 304-core Dell Linux cluster at IIT, using 8 k-points and the B3LYP functional, and took ~14 days.
B. Cefdinir sesquihydrate
N-TREOR, DICVOL as incorporated into FOX, and JADE 9.8 (MDI, 2017) indexed the pattern on centered monoclinic unit cells. We chose to use the C-centered setting with a = 23.987, b = 5.016, c = 15.920 Å, β = 109.45°, V = 1807.0 Å3, and Z = 4. Analysis of potential space groups suggested C2, which was confirmed by successful solution and refinement. A reduced cell search in the Cambridge Structural Database (Groom et al., Reference Groom, Bruno, Lightfoot and Ward2016) combined with the chemistry C, H, N, O, and S yielded no hits. The structure was solved with FOX using a cefdinir molecule and two oxygen atoms (water molecules) as fragments. 93 cycles of simulated annealing, with one million moves per cycle, were carried out. One of the runs had a cost factor (~105 000) much lower than the others (~150 000). One of the two oxygen atoms moved too close to the cefdinir molecule, and was discarded. A difference Fourier map yielded a peak on the two-fold axis showing that the compound is actually a sesquihydrate. A second FOX run yielded a similar structure, but with the carboxylic acid and oxime rotated about 180° from the first solution. Both the refinement residuals and the DFT optimized energy for the second solution were much lower than those for the first solution.
Rietveld refinement was carried out using GSAS (Toby, Reference Toby2001; Larson and Von Dreele, Reference Larson and Von Dreele2004). Only the 1.0–25.0° portion of the pattern was included in the refinement (d min = 0.957 Å). All non-H bond distances and angles were subjected to restraints, based on a Mercury/Mogul Geometry Check (Bruno et al., Reference Bruno, Cole, Kessler, Luo, Motherwell, Purkis, Smith, Taylor, Cooper, Harris and Orpen2004; Sykes et al., Reference Sykes, McCabe, Allen, Battle, Bruno and Wood2011) of the molecule. The Mogul average and standard deviation for each quantity were used as the restraint parameters. The restraints contributed 6.1% to the final χ 2. The hydrogen atoms were included in calculated positions, which were recalculated during the refinement using Materials Studio (Dassault, 2018). Positions of the active hydrogens were derived by analysis of potential hydrogen bonding patterns. A common U iso was refined for the non-H atoms of the fused-ring system, another U iso for the thiazole ring, another for the center of the molecule, another U iso for the carboxylic acid, another U iso for the ethylene substituent, and another U iso for the water molecules. The U iso for each hydrogen atom was constrained to be 1.3 × that of the heavy atom to which it is attached. The peak profiles were described using profile function #4 (Thompson et al., Reference Thompson, Cox and Hastings1987; Finger et al., Reference Finger, Cox and Jephcoat1994), which includes the Stephens (Reference Stephens1999) anisotropic strain broadening model. The background was modeled using a 3-term shifted Chebyshev polynomial, with a 4-term diffuse scattering function to model the Kapton capillary and any amorphous component. A 2nd-order spherical harmonic preferred orientation model was included in the refinement; the texture index was 1.0007, indicating that preferred orientation was not significant in this rotated capillary specimen.
The final refinement of 117 variables using 24 072 observations (24 002 data points and 70 restraints) yielded the residuals Rwp = 0.0669, Rp = 0.0540, and χ 2 = 1.301. The largest peak (1.44 Å from O14) and hole (1.84 Å from C22) in the difference Fourier map were 0.23 and −0.20 eÅ−3, respectively. The Rietveld plot is included as Figure 5. The largest errors in the fit are in the positions, shapes, and intensities of some of the strong, low angle peaks, perhaps reflecting some beam damage.
(Color online) The Rietveld plot for the refinement of cefdinir sesquihydrate. The black crosses represent the observed data points, and the red line is the calculated pattern. The blue curve is the difference plot, plotted at the same scale as the other patterns. The row of magenta tick marks indicates the calculated reflection positions. The vertical scale has been multiplied by a factor of 3 for 2θ > 7.2° and by a factor of 20 for 2θ > 12.2°.
A density functional geometry optimization (fixed experimental unit cell) was carried out using VASP (Kresse and Furthmüller, Reference Kresse and Furthmüller1996). The calculation used the GGA-PBE functional, a plane wave cutoff energy of 400.0 eV, and a k-point spacing of 0.5 Å−1 leading to a 6 × 6 × 1 mesh. The calculation was carried out on 16 2.4 GHz processors (each with 4 Gb RAM) of a 64-processor HP Proliant DL580 Generation 7 Linux cluster at North Central College, and took ~28 h. A density functional geometry optimization was also carried out using CRYSTAL14 (Dovesi et al., Reference Dovesi, Orlando, Erba, Zicovich-Wilson, Civalleri, Casassa, Maschio, Ferrabone, De La Pierre, D-Arco, Noël, Causà and Kirtman2014). The basis sets for the H, C, N, and O atoms were those of Gatti et al. (Reference Gatti, Saunders and Roetti1994), and the basis set for S was that of Bredow et al. (Reference Bredow, Heitjans and Wilkening2004). The calculation was run on eight 2.1 Ghz Xeon cores (each with 6 Gb RAM) of a 304-core Dell Linux cluster at IIT, using 8 k-points and the B3LYP functional, and took ~14 days.
III. RESULTS AND DISCUSSION
The powder pattern of the anhydrous cefdinir examined here matches that of Figure 1 of US Patent Application 2005/0059818 (Duerst et al., Reference Duerst, Law and Lou2005; Abbott) well enough to conclude that it is Form I (Figure 6). The powder pattern of cefdinir sesquihydrate matches that reported for cefdinir under uncontrolled relative humidity (Figure 7; Ohnishi et al., Reference Ohnishi, Deguchi and Kitamura2008; Astellas). The refined atom coordinates of cefdinir and cefdinir sesquihydrate and the coordinates from the DFT optimizations are reported in the CIFs attached as Supplementary Material.
(Color online) Comparison of the synchrotron powder pattern of anhydrous cefdinir to that of crystalline Form I from US Patent application 2005/0059818 (Duerst et al., Reference Duerst, Law and Lou2005; Abbott). The literature pattern (measured using Cu Kα radiation) was digitized using UN-SCAN-IT (Silk Scientific, 2013) and re-scaled to the synchrotron wavelength of 0.414157 Å using Jade 9.8 (MDI, 2017).
(Color online) Comparison of the synchrotron powder pattern of cefdinir sesquihydrate to that of cefdinir measured under uncontrolled humidity from US Patent 7,351419 Fig. 3 (Ohnishi et al., Reference Ohnishi, Deguchi and Kitamura2008; Astellas). The literature pattern (measured using Cu Kα radiation) was digitized using UN-SCAN-IT (Silk Scientific, 2013) and re-scaled to the synchrotron wavelength of 0.413342 Å using Jade 9.8 (MDI, 2017).
A. Cefdinir
The optimized structures from VASP and CRYSTAL14 are compared in Figure 8. The structures are almost identical. The RMSD is only 0.0646 Å. The root-mean-square Cartesian displacement of the experimental and the crystal optimized structures for non-hydrogen atoms in the cefdinir molecules is 0.2498 Å (Figure 9). The largest deviations are in the ethylene substituent of the molecule. The excellent agreement between the refined and optimized structures is evidence that the experimental structure is correct (van de Streek and Neumann, Reference van de Streek and Neumann2014). This discussion will concentrate on the CRYSTAL optimized structure. The asymmetric unit (with atom numbering) is illustrated in Figure 10, and the crystal structure is presented in Figure 11.
(Color online) Comparison of the CRYSTAL14- (blue) and VASP-optimized (green) structures of anhydrous cefdinir.
(Color online) Comparison of the Rietveld-refined (red) and CRYSTAL14-optimized (blue) structures of anhydrous cefdinir.
(Color online) The asymmetric unit of anhydrous cefdinir, with the atom numbering. The atoms are represented by 50% probability spheroids.
(Color online) The crystal structure of anhydrous cefdinir, viewed down the a-axis.
Almost all of the bond distances and bond angles fall within the normal ranges indicated by a Mercury Mogul Geometry check (Macrae et al., Reference Macrae, Bruno, Chisholm, Edington, McCabe, Pidcock, Rodriguez-Monge, Taylor, van de Streek and Wood2008). The angle C16-C2-C1 (119.3°; average = 122.1(8); Z-score = 3.3). is flagged as unusual and the Z-score results from the low standard deviation on the average angle. The torsion angle O23-C21-C1-C2 is flagged as unusual. This torsion angle describes the orientation of the carboxylic acid group. The distribution of the few similar torsion angles in the CSD is fairly wide, similar to the distributions of carboxylic acid groups in citrates (Rammohan and Kaduk, Reference Rammohan and Kaduk2018). The torsion angles around the C25–C27 bond are all unusual. As an example, the O26-C25-C27-C31 torsion is expected to be near 180° but it is 28°.
Analysis of the contributions to the total crystal energy of anhydrous cefdinir using the Forcite module of Materials Studio (Dassault, 2018) suggests that angle and torsion distortion terms are significant in the intramolecular deformation energy, as might be expected from a fused ring system. The intermolecular energy is very small. The hydrogen bonds are better analyzed using the results of the DFT calculation.
The oxime O29-H30 acts as an intermolecular hydrogen bond donor to O22, the carbonyl oxygen of the carboxylic acid (Table I). The energy of this hydrogen bond is calculated using the correlation of Rammohan and Kaduk (Reference Rammohan and Kaduk2018). Surprisingly, the carboxylic acid O23 does not act as a donor to an electronegative atom, but to the doubly-bonded carbon C18. The amino group N37 acts as a donor in two intermolecular hydrogen bonds to O22 and N28. The energy of the N-H···O hydrogen bond was calculated according to the correlation of Wheatley and Kaduk (Reference Wheatley and Kaduk2018). The amide N13-H14 makes an intramolecular hydrogen bond to the oxime oxygen O29. There are several intra- and intermolecular C-H···O hydrogen bonds, as well as an intramolecular N-H···S hydrogen bond. Presumably, these intramolecular hydrogen bonds help define the conformation of this molecule.
Hydrogen bonds (CRYSTAL14) in cefdinir.
a = intramolecular.
B. Cefdinir sesquihydrate
The optimized structures from VASP and CRYSTAL14 are compared in Figure 12. The structures are almost identical. The RMSD is only 0.0342 Å. This discussion concentrates on the CRYSTAL-optimized structure. The root-mean-square Cartesian displacement of the experimental and the crystal optimized structures for non-hydrogen atoms in the cefdinir molecules is 0.0952 Å (Figure 13). The largest deviations are in the outer portions of the molecule. The excellent agreement between the refined and optimized structures is evidence that the experimental structure is correct (van de Streek and Neumann, Reference van de Streek and Neumann2014). This discussion will concentrate on the CRYSTAL optimized structure. The asymmetric unit (with atom numbering) is illustrated in Figure 14, and the crystal structure is presented in Figure 15.
(Color online) Comparison of the CRYSTAL14- (blue) and VASP-optimized (green) structures of cefdinir sesquihydrate.
(Color online) Comparison of the Rietveld-refined (red) and CRYSTAL14-optimized (blue) structures of cefdinir sesquihydrate.
(Color online) The asymmetric unit of cefdinir sesquihydrate, with the atom numbering. The atoms are represented by 50% probability spheroids.
(Color online) The crystal structure of cefdinir sesquihydrate, viewed down the b-axis.
All of the bond distances and bond angles fall within the normal ranges indicated by a Mercury Mogul Geometry check (Macrae et al., Reference Macrae, Bruno, Chisholm, Edington, McCabe, Pidcock, Rodriguez-Monge, Taylor, van de Streek and Wood2008). The torsion angle O8-C7-C9-C16 of 29.3° is flagged as unusual, and occurs in a minor population of similar torsion angles. The torsion angles around the C16–C18 bond are all unusual, but not unprecedented.
Analysis of the contributions to the total crystal energy of the sesquihydrate using the Forcite module of Materials Studio (Dassault, 2018) suggests that angle and torsion distortion terms are significant in the intramolecular deformation energy, as might be expected from a fused ring system. The intermolecular energy is dominated by electrostatic attractions, which in this force-field-based analysis include hydrogen bonds. The hydrogen bonds are better analyzed using the results of the DFT calculation.
The carboxylic acid O15-H35 makes a strong intermolecular hydrogen bond to N24, the nitrogen of the thiazole ring (Table II). The oxime O20-H36 makes a strong hydrogen bond to the water molecule O40. The amide hydrogen H31 forms an intermolecular hydrogen bond to the amide oxygen O17; the graph set (Etter, Reference Etter1990; Bernstein et al., Reference Bernstein, Davis, Shimoni and Chang1995; Shields et al., Reference Shields, Raithby, Allen and Motherwell2000) is C1,1(4) and the chains run along the b-axis. The amine nitrogen N26 acts as a donor in two intermolecular hydrogen bonds. One to O14, the carbonyl of the carboxylic acid. The other to O10, the carbonyl on the four-membered ring. O41, the water molecule on the two-fold axis, bridges two cefdinir molecules each through O10. The water molecule, O41, acts as a donor to O15, the O-H of the carboxylic acid, and to N24. Several C-H···O hydrogen bonds also contribute to the crystal energy.
Hydrogen bonds (CRYSTAL14) in cefdinir sesquihydrate.
a = intramolecular.
The cefdinir molecules in the anhydrous crystal structure and sesquihydrate have very different conformations (Figure 16). Quantum chemical geometry optimizations (DFT/6-31G*/B3LYP/water) using Spartan '16 (Wavefunction, 2017) indicate that the conformation in anhydrous cefdinir is lower in energy than in the sesquihydrate, but only by 1.6 kcal mol−1. Within the uncertainties of such calculations the two conformations are essentially equivalent in energy.
(Color online) Comparison of the cefdinir conformation in anhydrous cefdinir (green) and cefdinir sesquihydrate (blue).
Quantum chemical geometry optimizations (DFT/6-31G*/B3LYP/water) using Spartan '16 (Wavefunction, 2017) indicated that the observed conformations of cefdinir in both phases are about 6.5 kcal mole−1 higher in energy than the local minimum energy conformations. Molecular mechanics conformational analysis indicated that the global minimum energy conformation has a more compact conformation with the ring systems roughly parallel to each other, and thus that intermolecular interactions are important in determining the solid state conformation.”
The CRYSTAL14 energy of anhydrous cefdinir is −1896.528472 eV molecule−1. The energy of a water molecule is −76.417975 eV molecule−1. The energy of cefdinir sesquihydrate is −2101.407257 eV molecule−1, 90.251822 eV molecule−1 less than the sum of cefdinir plus 1.5 water. Presumably most of the “extra” energy comes from the additional hydrogen bonds in the sesquihydrate. The only common hydrogen bond in the two structures is the intramolecular one between the amide nitrogen and the oxime oxygen, so it is difficult to attribute the energy to particular hydrogen bonds.
The volume enclosed by the Hirshfeld surface (Figure 17; Hirshfeld, Reference Hirshfeld1977; Turner, et al., Reference Turner, McKinnon, Wolff, Grimwood, Spackman, Jayatilaka and Spackman2017) of anhydrous cefdinir is 392.31 Å3, 98.07% of 1/2 the unit cell volume. The molecules are thus not tightly packed. All of the significant close contacts (red in Figure 17) involve the hydrogen bonds. The volume enclosed by the Hirshfeld surface (Figure 18) of cefdinir sesquihydrate is 454.82 Å3, 100.71% of 1/4 the unit cell volume. The molecules are thus tightly packed, the result of the hydrogen bonding. All of the significant close contacts (red in Figure 18) involve the hydrogen bonds.
(Color online) The Hirshfeld surface of anhydrous cefdinir. Intermolecular contacts longer than the sums of the van der Waals radii are colored blue, and contacts shorter than the sums of the radii are colored red. Contacts equal to the sums of radii are white.
(Color online) The Hirshfeld surface of cefdinir sesquihydrate. Intermolecular contacts longer than the sums of the van der Waals radii are colored blue, and contacts shorter than the sums of the radii are colored red. Contacts equal to the sums of radii are white.
The Bravais-Friedel-Donnay-Harker (Bravais, Reference Bravais1866; Friedel, Reference Friedel1907; Donnay and Harker, Reference Donnay and Harker1937) morphology suggests that we might expect needle-like morphology for cefdinir sesquihydrate, with <010> as the long axis. The same calculation for anhydrous cefdinir yields a block morphology with {020} as major faces. Examination of Figures 2(a)–2(e) and 3(a)–3(e) suggest that some of these patterns exhibit preferred orientation. The refined texture indices for the current data sets were close to unity, showing that preferred orientation was not significant for these specimens. The powder patterns of cefdinir and cefdinir sesquihydrate are included in the Powder Diffraction File™ as entries 00-066-1604 and 00-066-1605 respectively.
SUPPLEMENTARY MATERIAL
The supplementary material for this article can be found at https://doi.org/10.1017/S0885715619000459
ACKNOWLEDGEMENTS
We thank Lynn Ribaud and Saul Lapidus for their assistance in the data collection, and Andrey Rogachev for the use of computing resources at IIT. Use of the Advanced Photon Source at Argonne National Laboratory was supported by the U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357.
FUNDING DETAILS
This work was partially supported by the International Centre for Diffraction Data.
CONFLICTS OF INTEREST
The authors have no conflicts of interest to declare.
