Crystal structure of meglumine diatrizoate, (C7H18NO5)(C11H8I3N2O4)

The crystal structure of meglumine diatrizoate has been solved and refined using synchrotron X-ray powder diffraction data and optimized using density functional theory techniques. Meglumine diatrizoate crystallizes in space group P21 (#4) with a = 10.74697(4), b = 6.49364(2), c = 18.52774(7) Å, β = 90.2263(3), V = 1292.985(5) Å3, and Z = 2. Two different crystal structures, which yielded essentially identical refinement residuals and positions of the non-H atoms, were obtained. The differences were in the H atom positions and the hydrogen bonding. One structure was 123.0 kJ/mol/cell lower in energy than the other and was adopted for the final description. The crystal structure consists of alternating double layers of cations and anions along the c-axis. The hydrogen bonds link the cations and anions into a three-dimensional framework. Each of the hydrogen atoms on the ammonium nitrogen of the cation acts as a donor in a strong N–H⋯O hydrogen bond. One of these is to a hydroxyl group of another cation, and the other is to the carboxylate group of the anion. Each of the amide nitrogen atoms of the anion forms a strong N–H⋯O intermolecular hydrogen bond, one to a carbonyl and the other to a carboxylate group. The powder pattern has been submitted to ICDD for inclusion in the Powder Diffraction File™ (PDF®).


I. INTRODUCTION
Meglumine diatrizoate (combined with diatrizoate sodium and sold under the brand name Renografin-60 and Gastrografin, among others) is a common colorless liquid contrast agent used in radiography, commonly of the urinary tract and parts of the digestive system, and is administered orally or intravascularly (Geng et al., 2018).The systematic name (CAS Registry Number 131-49-7) is (2R,3R,4R,5S)-6-(methylammonium)hexane-1,2,3,4,5-pentol 3,5-diacetamido-2,4,6-triiodobenzoate.For children and adults, 660 mg/ml of meglumine diatrizoate is used with 100 mg/ml diatrizoate sodium as an injection and is named MD-76R by the FDA (Dizendorf et al., 2002;FDA.gov, 2017).There are a number of possible side effects of MD-76R, including a decrease in urine production or blood in urine, burning sensation and pain during urination, dizziness, increased heart rate, and others (Mayo Clinic, 2022).The effect of nephrotoxicity due to meglumine diatrizoate and other contrast agents has also been presented, particularly in angioplasty and angiography (Berns, 1989).A twodimensional molecular diagram is shown in Figure 1.
Meglumine diatrizoate is claimed as a component of oral contrast agents in US Patent 7,384,624 B2 (Raines, 2008) and is described as useful in radiosurgery of tumors in US Patent Application 2004/0006254 A1 (Weil and Morris, 2004).We are unaware of any published X-ray powder diffraction data on meglumine diatrizoate.
This work was carried out as part of a project (Kaduk et al., 2014) to determine the crystal structures of large-volume commercial pharmaceuticals and include high-quality powder diffraction data for them in the powder diffraction file (PDF) (Gates-Rector and Blanton, 2019).

II. EXPERIMENTAL
Meglumine diatrizoate was a commercial reagent, purchased from Sigma (Batch #SLCJ2134), and was used asreceived.The white powder was packed into a 1.5 mm diameter Kapton capillary and rotated during the measurement at ∼50 Hz.The powder pattern was measured at 295 K at beam line 11-BM (Antao et al., 2008;Lee et al., 2008;Wang et al., 2008) of the Advanced Photon Source at Argonne National Laboratory using a wavelength of 0.458963(2) Å from 0.5 to 50°2θ with a step size of 0.001°a nd a counting time of 0.1 s/step.The high-resolution powder diffraction data were collected using 12 silicon crystal analyzers that allow for high angular resolution, high precision, and accurate peak positions.A mixture of silicon (NIST SRM 640c) and alumina (NIST SRM 676a) standards (ratio Al 2 O 3 :Si = 2:1 by weight) was used to calibrate the instrument and refine the monochromatic wavelength used in the experiment.The beamline staff noted that the meglumine diatrizoate specimen changed slightly during the measurement.
The synchrotron diffraction pattern was indexed using N-TREOR (Altomare et al., 2013) on a high-quality primitive monoclinic unit cell with a = 10.74782,b = 6.49318, c = 18.53081Å, β = 90.206°,V = 1293.2Å 3 , and Z = 2.A reduced cell search of the Cambridge Structural Database (Groom et al., 2016) with the chemistry C, H, I, N, and O only, yielded no hits.
The meglumine cation was extracted from the previously mentioned HUTMAK crystal structure using Materials Studio (Dassault Systèmes, 2021), and saved as a *.mol2 file.This file was converted to a Fenske-Hall Z-matrix using OpenBabel (O'Boyle et al., 2011).The diatrizoate anion was built using Spartan '18 (Wavefunction, 2020), saved as a *.mol2 file, and converted using the same tools as for the cation.
The structure was solved using Monte Carlo simulated annealing techniques as implemented in EXPO2014 (Altomare et al., 2013) andFOX (Favre-Nicolin andC ̌erný, 2002).Two different structures (structures 1 and 2) were obtained.Both had similar arrangements of heavy (non-H) atoms, but different apparent H-bonding patterns.We refined and optimized both structures.Although both structures refined to similar residuals (R wp = 0.04566 and 0.04556 and goodness of fit (GOF) = 1.58 and 1.57 for structures 1 and 2, respectively), the (VASP) energy of structure 2 was 123.0 kJ/mol/cell lower in energy than that of structure 1, so is the one primarily discussed here.
Rietveld refinement was carried out using general Structure Analysis System (GSAS)-II (Toby and Von Dreele, 2013).Only the 1.0-30.0°portion of the pattern was included in the refinement (d min = 0.887 Å).All non-H bond distances and angles were subjected to restraints, based on a Mercury/Mogul Geometry check (Bruno et al., 2004;Sykes et al., 2011).The Mogul average and standard deviation for each quantity were used as the restraint parameters.The restraints contributed 1.7% to the final χ 2 .The hydrogen atoms were included in calculated positions, which were recalculated during the refinement using Materials Studio (Dassault Systèmes, 2021).The I atoms were refined anisotropically.The U iso of the heavy atoms was grouped by chemical similarity.The U iso for the H atoms was fixed at 1.3× the U iso of the heavy atoms to which they are attached.No preferred orientation model was included in the refinement.The peak profiles were described using the generalized microstrain model (Stephens, 1999).The background was modeled using a sixterm shifted Chebyshev polynomial, and a peak at 6.18°2θ to model the scattering from the Kapton capillary and an amorphous component.
The final refinement of 141 variables using 29,047 observations and 76 restraints yielded the residuals R wp = 0.0456 and GOF = 1.57.The largest peak (1.65 Å from O48) and hole (1.47 Å from I38) in the difference Fourier map were 0.37(9) and -0.41(9) eÅ −3 , respectively.The largest errors in the difference plot (Figure 2) are in the shapes of some of the low-angle peaks, perhaps reflecting the specimen changes noted by the beamline staff.
Both structures of meglumine diatrizoate were optimized (fixed experimental unit cell) with density functional techniques using VASP (Kresse and Furthmüller, 1996) through the MedeA graphical interface (Materials Design, 2016).The calculations were 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.The calculation used the generalized gradient approximation (GGA)-Perdew-Burke-Ernzerhof (PBE) functional, a plane wave cutoff energy of 400.0 eV, and a k-point spacing of 0.5 Å −1 leading to a 2 × 2 × 1 mesh, and took ∼19 (structure 1) and 10 (structure 2) hours.Single-point density functional calculations (fixed experimental cell) and population analysis were carried out using CRYSTAL17 (Dovesi et al., 2018).The basis sets for the H, C, N, and O atoms in the calculation were those of Gatti et al. (1994), and for I was that of Laun and Bredow (2022).The calculations were run on a 3.5 GHz PC using 8 k-points and the B3LYP functional and took ∼2.8 h.

III. RESULTS AND DISCUSSION
Two different crystal structures of meglumine diatrizoate, which yielded essentially identical refinement residuals and positions of the non-H atoms, were obtained.The orientations of four of the five hydroxyl groups (O1, O2, O3, and O4) in the meglumine cation differ between the two structures (Figure 3).Some of the atoms have different names in the two structures.There is an additional complication in describing the structures.The chemical connectivity of the anion exhibits two-fold rotational symmetry, but the atom names are arbitrary.Superposition of the anions of the two structures (Figure 4) reveals that the structure solutions oriented the anions differently, so that chemically-equivalent atoms bear different atom numbers in the two structures.The DFT calculations indicated that structure 2 was significantly lower in energy, so is preferred and the one on which this discussion concentrates.
The root-mean-square Cartesian displacement between the Rietveld-refined and DFT-optimized cations is 0.084 Å Figure 2. The Rietveld plot for the refinement of meglumine diatrizoate.The blue crosses represent the observed data points, and the green line is the calculated pattern.The cyan curve is the normalized error plot, and the red line is the background curve.The vertical scale has been multiplied by a factor of 8× for 2θ > 12.0°.(Figure 5).The maximum deviation is 0.114 Å, at the methyl group C7.The similar quantities for the anion are 0.053 Å (Figure 6) and 0.100 Å, at C47.The excellent agreement is well within the normal range for correct structures (van de Streek and Neumann, 2014) and provides strong evidence that the refined structure is correct.The asymmetric unit (with atom numbering) is illustrated in Figure 7.   Figure 7.The asymmetric unit of meglumine diatrizoate, with the atom numbering.The atoms are represented by 50% probability spheroids/ellipsoids. Image generated using Mercury (Macrae et al., 2020).
3,-3,10.The Mercury Aromatics Analyser indicates only two weak interactions with distances of 6.49 and 7.14 Å between the phenyl rings of the anions.
All of the bond distances, bond angles, and torsion angles fall within the normal ranges indicated by a Mercury Mogul Geometry check (Macrae et al., 2020).Quantum chemical geometry optimization of the isolated cation and anion (DFT/ B3LYP/6-31G*/water) using Spartan '20 (Wavefunction, 2022) indicated that the observed conformation of the cation is close to a local minimum.The global minimum-energy conformation of the cation differs significantly (Figure 9), and is 41.7 kJ/mol lower in energy.The observed conformation of the anion is very close to a local minimum.The global minimum-energy conformation of the anion is 20.7 kJ/mol lower in energy, and has a very different conformation (Figure 10).The differences are mainly in the conformations of the amide side chains.The differences indicate that intermolecular interactions are important in determining the solid-state conformation.Analysis of the contributions to the total crystal energy of the structure using the Forcite module of Materials Studio (Dassault Systèmes, 2021) suggests that torsion distortion terms dominate the intramolecular deformation energy.The intermolecular energy is dominated by electrostatic attractions, which in this force field analysis also include hydrogen bonds.The hydrogen bonds are better analyzed using the results of the DFT calculation.
Hydrogen bonds are prominent in the crystal structure (Table I).Each of the hydrogen atoms on the ammonium  nitrogen N6 of the cation acts as a donor in a strong N-H⋯O hydrogen bond.One of these is to a hydroxyl group O2 of another cation, and the other is to the carboxylate O43 of the anion.The energies of the N-H⋯O hydrogen bonds were calculated using the correlation of Wheatley and Kaduk (2019).Each of the amides N44 and N45 of the anion forms a strong N-H⋯O intermolecular hydrogen bond, one to a carbonyl O49 and the other to a carboxylate O42.Thus, each O of the carboxylate acts as an acceptor in an N-H⋯O hydrogen bond.There is a variety of O-H⋯O hydrogen bonds between the hydroxyl groups of the cation.Some are intramolecular to other hydroxyl groups, and others are intermolecular, both to hydroxyl groups and to carboxyl and carbonyl groups.The energies of the O-H⋯O hydrogen bonds were calculated using the correlation of Rammohan and Kaduk (2018).Several C-H⋯O hydrogen bonds also contribute to the lattice energy.C-I⋯O halogen bonds (Table II; Corradi et al., 2000;Wilcken et al., 2013) also apparently contribute to the crystal energy.
The volume enclosed by the Hirshfeld surface of the meglumine diatrizoate asymmetric unit (Figure 11, Hirshfeld, 1977;Spackman et al., 2021) is 637.73Å 3 , 98.64% of 1/2 the unit cell volume.The packing density is thus fairly typical.The only significant close contacts (red in Figure 11) involve the hydrogen bonds.The volume/nonhydrogen atom is larger than normal, at 19.6 Å 3 , reflecting the presence of the large I atoms.
The Bravais-Friedel-Donnay-Harker (Bravais, 1866;Friedel, 1907;Donnay and Harker, 1937) morphology suggests that we might expect platy morphology for meglumine diatrizoate, with {001} as the principal faces.No preferred orientation model was necessary, indicating that preferred orientation was not present in this rotated capillary specimen.

IV. DEPOSITED DATA
The powder pattern of meglumine diatrizoate from this synchrotron data set has been submitted to ICDD for inclusion in the PDF.The Crystallographic Information Framework (CIF) files containing the results of the Rietveld refinement (including the raw data) and the DFT geometry optimization were deposited with the ICDD.The data can be requested at pdj@icdd.com.

Figure 3 .
Figure 3.Comparison of the structure of the cation in the correct (low-energy) structure (green) and the incorrect (high-energy) structure (purple).Image generated using Mercury (Macrae et al., 2020).

Figure 4 .
Figure 4. Comparison of the structure of the anion in the correct (low-energy) structure (green) and the incorrect (high-energy) structure (purple).Image generated using Mercury (Macrae et al., 2020).

Figure 8 .
Figure 8.The crystal structure of meglumine diatrizoate, viewed down the b-axis.Image generated using Diamond (Crystal Impact, 2022).

Figure 9 .
Figure 9.Comparison of the observed structure of the meglumine cation (blue) to the global minimum-energy conformation (orange).Image generated using Mercury (Macrae et al., 2020).

Figure 10 .
Figure 10.Comparison of the observed structure of the diatrizoate anion (blue) to the global minimum-energy conformation (orange).Image generated using Mercury (Macrae et al., 2020).

Figure 11 .
Figure11.The Hirshfeld surface of meglumine diatrizoate.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.Image generated using CrystalExplorer(Spackman et al., 2021).

TABLE I .
Hydrogen bonds (CRYSTAL17) in the two structure solutions of meglumine diatrizoate.
The top lines are structure 1 (incorrect/higher energy) and the bottom lines are structure 2 (correct/lower energy).XXX structure 1 to structure 2 equivalent names.a Intramolecular.