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Crystal structure of loteprednol etabonate Form II, C24H31ClO7

Published online by Cambridge University Press:  19 January 2021

James A. Kaduk Open the ORCID record for James A. Kaduk [Opens in a new window] ,
Amy M. Gindhart  and
Thomas N. Blanton Open the ORCID record for Thomas N. Blanton [Opens in a new window]
James A. Kaduk*
Affiliation:
Illinois Institute of Technology, 3101 S. Dearborn St., Chicago, Illinois 60616, USA North Central College, 131 S. Loomis St., Naperville, Illinois 60540, USA
Amy M. Gindhart
Affiliation:
ICDD, 12 Campus Blvd., Newtown Square, Pennsylvania 19073-3273, USA
Thomas N. Blanton
Affiliation:
ICDD, 12 Campus Blvd., Newtown Square, Pennsylvania 19073-3273, USA
*
a)Author to whom correspondence should be addressed. Electronic mail: kaduk@polycrystallography.com

Abstract

The crystal structure of loteprednol etabonate Form II has been solved and refined using synchrotron X-ray powder diffraction data, and optimized using density functional techniques. Loteprednol etabonate Form II crystallizes in the space group P21 (#4) with a = 11.96312(6), b = 14.91862(5), c = 6.75715(3) Å, β = 94.1584(3)°, V = 1202.796(6) Å3, and Z = 2. The crystal structure is characterized by herringbone layers in the ab-plane. The anisotropic displacement ellipsoid of the Cl atom is not oriented in a way which corresponds to a chemically sensible motion of this atom. The sample suffered damage in the X-ray beam, probably involving photolysis of the C–Cl bond. The most prominent hydrogen bond is the O–H⋯O hydrogen bond between the hydroxyl group and the carbonyl group of the steroid A ring. This hydrogen bond links the molecules into C1,1(9) chains along the b-axis. The powder pattern is included in the Powder Diffraction File™ (PDF®) as entry 00-066-1602; this study will allow inclusion of the atomic coordinates to the PDF entry.

Keywords

loteprednol etabonateAlrexpowder diffractionRietveld refinementdensity functional theory

Information

Type
New Diffraction Data
Information
Powder Diffraction , Volume 36 , Issue 1 , March 2021 , pp. 50 - 55
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Copyright
Copyright © The Author(s), 2021. Published by Cambridge University Press on behalf of International Centre for Diffraction Data

I. INTRODUCTION

Loteprednol etabonate, sold as a suspension under the brand names Alrex and Lotemax, is an ophthalmic analog of the corticosteroid prednisolone with anti-inflammatory activity. Loteprednol works by relieving symptoms such as swelling, redness, and itching because of eye injury or surgery. The IUPAC name (CAS Registry number 82034-46-6) is chloromethyl (8S,9S,10R,11S,13S,14S,17R)-17-ethoxycarbonyloxy-11-hydroxy-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-17-carboxylate. A two-dimensional molecular diagram is shown in Figure 1.

Figure 1.

The molecular structure of loteprednol etabonate.

A star-quality powder pattern (no atomic coordinates) based on a Le Bail extraction of the synchrotron data set discussed in this work is included in the Powder Diffraction File (Gates-Rector and Blanton, Reference Gates-Rector and Blanton2019) as entry 00-066-1602. Chinese Patent Application CN106892952A (Wang et al., Reference Wang, Han and Xiu2015a) claims crystalline Form I of loteprednol etabonate and reports powder diffraction data for Form II, which is described as the conventional form. Crystalline loteprednol monohydrate is claimed in Chinese Patent Application CN106892953 (Wang et al., Reference Wang, Han and Xiu2015b). Powder patterns of mixtures of loteprednol etabonate and poly(D,L-lactic acid) are reported in Pinto (Reference Pinto2008).

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.

II. EXPERIMENTAL

Loteprednol etabonate was a commercial reagent, purchased from Sigma Aldrich (Lot #112M4712V), and was used as-received. 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 beamline 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 a wavelength of 0.414157 Å from 0.5 to 50° 2θ with a step size of 0.001° and a counting time of 0.1 s step−1. The beamline staff noted that the specimen exhibited darkening and that some (but not all) peaks decreased in intensity over a period of 800 s. The compound was apparently damaged in the beam.

The pattern was indexed on a primitive monoclinic unit cell with a = 11.969, b = 14.922, c = 6.760 Å, β = 94.2°, V = 1204.1 Å3, and Z = 2 using Jade 9.8 (MDI, 2018) and N-TREOR09 as implemented in EXPO2014 (Altomare et al., Reference Altomare, Cuocci, Giacovazzo, Moliterni, Rizzi, Corriero and Falcicchio2013). The suggested space group was P21, which was confirmed by successful solution and refinement of the structure. A reduced cell search in the Cambridge Structural Database (Groom et al., Reference Groom, Bruno, Lightfoot and Ward2016) yielded no hits and no structure for a loteprednol derivative. A loteprednol etabonate molecule was built using Spartan '18 (Wavefunction, 2018), and the minimum-energy conformation was established. The structure was solved with DASH (David et al., Reference David, Shankland, van de Streek, Pidcock, Motherwell and Cole2006) using the 1.8–13.6° portion of the pattern and including the Mogul Distribution bias on the 5 torsion angles. All of the runs converged on similar solutions.

Rietveld refinement was carried out using GSAS-II (Toby and Von Dreele, Reference Toby and Von Dreele2013). Only the 1.8–20.0° portion of the pattern was included in the refinement (d min = 1.192 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 results were exported to a CSV file. The Mogul average and standard deviation for each quantity were used as the restraint parameters, and were incorporated using the new feature Restraints/Edit Restraints/Add MOGUL Restraints, which read the bond distance and angle restraints from the CSV file. The restraints contributed 10.2% to the final χ 2. The hydrogen atoms were included in calculated positions, which were recalculated during the refinement using Materials Studio (Dassault Systèmes, 2018). The positions of the active hydrogen atoms were deduced by analysis of potential hydrogen-bonding patterns. The U iso of the non-H atoms were grouped by chemical similarity. A common U iso was refined for the non-H atoms of the steroid ring system, another U iso for the hydroxyl and methyl substituents on the ring system, and a third for the side chains. The U iso for each hydrogen atom was constrained to be 1.3× that of the heavy atom to which it is attached. The Cl atom was refined anisotropically. The background was modeled using a three-term shifted Chebyshev polynomial and a six-term diffuse scattering function to model the scattering from the Kapton capillary and any amorphous component.

The final refinement (begun from the result of the DFT calculation) of 137 variables using 18 202 observations and 90 restraints yielded the residuals Rwp = 0.1079 and Goodness Of Fit = 2.52. The largest peak (2.12 Å from C60, and perhaps indicating partial disorder of the Cl) and hole (2.07 Å from Cl63) in the difference Fourier map were 0.51 and −0.38(10) eÅ−3. The Rietveld plot is included in Figure 2. The largest errors in the fit are in the shapes and positions of some of the stronger peaks and probably represent the changes in the specimen during the measurement.

Figure 2.

The Rietveld plot for the refinement of loteprednol etabonate. The blue crosses represent the observed data points, and the green line is the calculated pattern. The cyan curve is the normalized error plot. The vertical scale has been multiplied by a factor of 20× for 2θ > 11.0°.

A density functional geometry optimization was 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, and O atoms were those of Gatti et al. (Reference Gatti, Saunders and Roetti1994), and the basis set for Cl was that of Peintinger et al. (Reference Peintinger, Vilela Oliveira and Bredow2013). 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 ~90 h.

III. RESULTS AND DISCUSSION

This synchrotron powder pattern of loteprednol etabonate matches those reported by Wang et al. (Reference Wang, Han and Xiu2015a) and Pinto (Reference Pinto2008) well enough to conclude that they correspond to the same material (Figure 3), which is Form II described by Wang et al. (Reference Wang, Han and Xiu2015a). The poor quality of the literature patterns makes a conclusive conclusion difficult, but the pattern of this study seems to be representative of materials studied by others.

Figure 3.

Comparison of the synchrotron pattern of loteprednol etabonate (this study; black) to the pattern of Form II from Wang et al. (Reference Wang, Han and Xiu2015a; black) and that of a 30% mixture of loteprednol etabonate and poly(D,L-lactic acid) from Pinto (Reference Pinto2008; red). The literature patterns (measured using CuKα radiation) were digitized using UN-SCAN-IT (Silk Scientific, 2013) and scaled to the synchrotron wavelength of 0.414157 Å using Jade 9.8 (MDI, 2018).

The refined atom coordinates of loteprednol etabonate and the coordinates from the DFT optimization are reported in the CIFs deposited with the ICDD. The root-mean-square Cartesian displacement of the non-hydrogen atoms in the Rietveld-refined and DFT-optimized structures is 0.201 Å (Figure 4), and the maximum displacement is 0.774 Å, at the methyl group C53 at the end of one of the side chains. The good agreement between the refined and optimized structures provides evidence that the experimental structure is correct (van de Streek and Neumann, Reference van de Streek and Neumann2014). This discussion concentrates on the CRYSTAL14-optimized structure. The asymmetric unit (with atom numbering) is illustrated in Figure 5, and the crystal structure is presented in Figure 6.

Figure 4.

Comparison of the Rietveld-refined (red) and CRYSTAL14-optimized (blue) structures of ioteprednol etabonate. The root-mean-square Cartesian displacement is 0.201 Å.

Figure 5.

The asymmetric unit of loteprednol etabonate, with the atom numbering. The atoms are represented by 50% probability spheroids/ellipsoids.

Figure 6.

The crystal structure of loteprednol etabonate, viewed down the c-axis.

The crystal structure is characterized by herringbone layers in the ab-plane (Figure 6). The anisotropic displacement ellipsoids of Cl63 are not oriented in a way, which corresponds to a chemically sensible motion of this atom. The orientation is reminiscent of that of the Br atom in bretylium tosylate (Wheatley et al., Reference Wheatley, Kaduk, Gindhart and Blanton2018), which also suffered from beam damage. Fixing the isotropic displacement parameter of Cl63 at a reasonable value and refining the occupancy yielded a value of 0.64, suggesting that the C–Cl bond photolyzed and that Cl left the crystal lattice.

All of the bond distances and bond angles and almost all of the torsion angles in the loteprednol etabonate molecule 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). Only the O58–C57–C39–C40 and O59–C57–C39–C40 torsion angles are flagged as unusual, but they lie on the tails of the minor component of a bimodal distribution and are not unprecedented.

Quantum chemical geometry optimization of the isolated loteprednol etabonate molecule (DFT/B3LYP/6-31G*/water) using Spartan '18 (Wavefunction, 2018) indicated that the observed solid-state conformation is 3.6 kcal mol−1 higher in energy than the local minimum. Molecular mechanics conformational analysis indicated that the observed conformation is 0.2 kcal mol−1 higher in energy than the global minimum-energy conformation, which has the chloromethyl group rotated ~180° from the observed conformation. The molecule is flexible, and apparently, solid-state interactions determine the observed conformation.

Analysis of the contributions to the total crystal energy using the Forcite module of Materials Studio (Dassault Systèmes, 2018) suggests that angle distortion terms are predominant in the intramolecular deformation energy, as might be expected for 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.

Only a few hydrogen bonds are present in the crystal structure (Table I). The most prominent is the O–H⋯O hydrogen bond between the hydroxyl group and the carbonyl group of the steroid A ring. The energy of this bond was calculated using the correlation of Rammohan and Kaduk (Reference Rammohan and Kaduk2018). This hydrogen bond has the graph set symbol C1,1(9) (Etter, Reference Etter1990; Bernstein et al., Reference Bernstein, Davis, Shimoni and Chang1995; Shields et al., Reference Shields, Raithby, Allen and Motherwell2000) and links the molecules into chains along the b-axis. C–H⋯Cl hydrogen bonds are present. Such bonds should help localize the Cl atom and suggest that the large displacement ellipsoid is not the result of thermal motion but partial occupancy from decomposition in the beam. Several C–H⋯O hydrogen bonds involve the oxygen atoms of the side chains. The hydroxyl group also acts as an acceptor in a C–H⋯O hydrogen bond.

Table I.

Hydrogen bonds (CRYSTAL14) in loteprednol etabonate.

The volume enclosed by the Hirshfeld surface (Figure 7; Hirshfeld, Reference Hirshfeld1977; Turner et al., Reference Turner, McKinnon, Wolff, Grimwood, Spackman, Jayatilaka and Spackman2017) is 593.30 Å3, 98.65% of one-fourth of the unit-cell volume. The molecules are thus not tightly packed. All of the significant close contacts (red in Figure 7) involve the hydrogen bonds. The volume/non-hydrogen atom is 18.8 Å3.

Figure 7.

The Hirshfeld surface of loteprednol etabonate. 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 elongated morphology for loteprednol etabonate, with 〈001〉 as the long axis, consistent with the anisotropy of the lattice parameters. A fourth-order spherical harmonic model was used to describe the preferred orientation. The texture index was 2.048, indicating that significant preferred orientation was present in this rotated capillary specimen. The powder pattern of loteprednol etabonate with atomic coordinates from this synchrotron data set is included in the Powder Diffraction File as entry 00-066-1602.

IV. DEPOSITED DATA

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 info@icdd.com.

ACKNOWLEDGEMENTS

The 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. This work was partially supported by the International Centre for Diffraction Data. 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.

CONFLICTS OF INTEREST

The authors have no conflicts of interest to declare.

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Figure 0

Figure 1. The molecular structure of loteprednol etabonate.

Figure 1

Figure 2. The Rietveld plot for the refinement of loteprednol etabonate. The blue crosses represent the observed data points, and the green line is the calculated pattern. The cyan curve is the normalized error plot. The vertical scale has been multiplied by a factor of 20× for 2θ > 11.0°.

Figure 2

Figure 3. Comparison of the synchrotron pattern of loteprednol etabonate (this study; black) to the pattern of Form II from Wang et al. (2015a; black) and that of a 30% mixture of loteprednol etabonate and poly(D,L-lactic acid) from Pinto (2008; red). The literature patterns (measured using CuKα radiation) were digitized using UN-SCAN-IT (Silk Scientific, 2013) and scaled to the synchrotron wavelength of 0.414157 Å using Jade 9.8 (MDI, 2018).

Figure 3

Figure 4. Comparison of the Rietveld-refined (red) and CRYSTAL14-optimized (blue) structures of ioteprednol etabonate. The root-mean-square Cartesian displacement is 0.201 Å.

Figure 4

Figure 5. The asymmetric unit of loteprednol etabonate, with the atom numbering. The atoms are represented by 50% probability spheroids/ellipsoids.

Figure 5

Figure 6. The crystal structure of loteprednol etabonate, viewed down the c-axis.

Figure 6

Table I. Hydrogen bonds (CRYSTAL14) in loteprednol etabonate.

Figure 7

Figure 7. The Hirshfeld surface of loteprednol etabonate. 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.